Compositions comprising methylphenidate-prodrugs, processes of making and using the same

ABSTRACT

The present technology is directed to compositions comprising d-threo-methylphenidate conjugates and unconjugated methylphenidate. The present technology also relates to compositions and oral formulations comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to a pharmaceutical kit containing the composition comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof.

RELATED APPLICATIONS

The present patent application is a continuation of U.S. patentapplication Ser. No. 16/431,422, filed on Jun. 4, 2019, which is acontinuation of U.S. patent application Ser. No. 16/431,275, filed onJun. 4, 2019, which is a continuation of PCT/US2017/065482, filed onDec. 9, 2017, and is related to and claims the priority benefit of U.S.Provisional Patent Application Ser. No. 62/541,695, filed Aug. 5, 2017,U.S. Provisional Patent Application Ser. No. 62/519,627, filed Jun. 14,2017, and U.S. Provisional Patent Application Ser. No. 62/432,675, filedDec. 11, 2016 the content of each of the aforementioned applicationswhich is hereby incorporated by reference in its/their entirety intothis disclosure.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Methylphenidate is a psychostimulant which is a chain substitutedamphetamine derivative. Similar to amphetamine and cocaine,methylphenidate targets the central nervous system, specifically thedopamine transporter (DAT) and norepinephrine transporter (NET).Methylphenidate is thought to act by increasing the concentrations ofdopamine and norepinephrine in the synaptic cleft, as methylphenidatehas both dopamine transporter (DAT) and norepinephrine transporter (NET)binding capabilities. Although an amphetamine derivative, thepharmacology of methylphenidate and amphetamine differ, as amphetamineis a dopamine transport substrate whereas methylphenidate works as adopamine transport blocker. As a norepinephrine and dopamine re-uptakeinhibitor, methylphenidate thus blocks re-uptake of dopamine andnorepinephrine (noradrenaline) into presynaptic neurons (and possiblystimulates the release of dopamine from dopamine nerve terminals at highdoses), thereby increasing the levels of dopamine and norepinephrine inthe synapse. In some in vitro studies, methylphenidate has been shown tobe more potent as an inhibitor of norepinephrine uptake/re-uptake whencompared to dopamine. However, some in vivo studies have indicated thatmethylphenidate is more potent in potentiating extracellular dopamineconcentrations than norepinephrine concentrations. Unlike amphetamine,it has been suggested in the scientific and/or clinical researchcommunity that methylphenidate does not seem to significantly facilitatethe release of these two monoamine neurotransmitters at therapeuticdoses.

Four isomers of methylphenidate are known to exist:d-erythro-methylphenidate, l-erythro-methylphenidate,d-threo-methylphenidate, and l-threo-methylphenidate. Originally,methylphenidate was marketed as a mixture of two racemates,d/l-erythro-methylphenidate and d/l-threo-methylphenidate. Subsequentresearch showed that most of the desired pharmacological activity of themixture is associated with the threo-isomer resulting in the marketingof the isolated threo-methylphenidate racemate. Later, the scientificcommunity determined that the d-threo-isomer is mostly responsible forthe stimulant activity. Consequently, new products were developedcontaining only d-threo-methylphenidate (also known as “d-threo-MPH”).

Stimulants, including methylphenidate (“MPH”), are believed to enhancethe activity of the sympathetic nervous system and/or central nervoussystem (CNS). Stimulants such as MPH and the various forms andderivatives thereof are used for the treatment of a range of conditionsand disorders predominantly encompassing, for example, attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),obesity, narcolepsy, appetite suppression, depression, anxiety and/orwakefulness.

Methylphenidate is currently approved by the United States Food and DrugAdministration (“FDA”) for the treatment of attention-deficithyperactivity disorder and narcolepsy. Methylphenidate has also shownefficacy for some off-label indications that include depression, obesityand lethargy. In some embodiments, the prodrugs of the presenttechnology may be administered for the treatment of attention-deficithyperactivity disorder and narcolepsy, or any condition that requiresthe blocking of the norepinephrine and/or dopamine transporters.

Attention deficit hyperactivity disorder (ADHD) in children has beentreated with stimulants for many years. However, more recently, anincrease in the number of prescriptions for ADHD therapy in the adultpopulation has, at times, outperformed the growth of the pediatricmarket. Although there are various drugs currently in use for thetreatment of ADHD, including some stimulants and some non-stimulantdrugs, methylphenidate (commercially available from, for example,Novartis International AG (located in Basel, Switzerland) under thetrademark Ritalin®) is commonly prescribed. Moreover, during classroomtrials, non-stimulants have shown to be less effective in improvingbehavior and attention of ADHD afflicted children than amphetaminederivatives.

Behavioral deterioration (rebound or “crashing”) is observed in asignificant portion of children with ADHD as the medication wears off,typically in the afternoon or early evening. Rebound symptoms include,for example, irritability, crankiness, hyperactivity worse than in theun-medicated state, sadness, crying, and in rare cases psychoticepisodes. The symptoms may subside quickly or last several hours. Somepatients may experience rebound/crashing so severe that treatment mustbe discontinued. Rebound/crashing effects can also give rise toaddictive behavior by enticing patients to administer additional dosesof stimulant with the intent to prevent anticipated rebound/crashingnegative outcomes and side effects.

Stimulants, such as methylphenidate and amphetamine, have been shown inthe conventional art to exhibit noradrenergic and dopaminergic effectsthat can lead to cardiovascular events comprising, for example,increased heart rate, hypertension, palpitations, tachycardia and inisolated cases cardiomyopathy, stroke, myocardial infarction and/orsudden death. Consequently, currently available stimulants exposepatients with pre-existing structural cardiac abnormalities or othersevere cardiac indications to even greater health risks and arefrequently not used or used with caution in this patient population.

Methylphenidate, like other stimulants and amphetamine derivatives, canbecome addictive and is prone to substance abuse. Oral abuse has beenreported, and euphoria can be achieved through intranasal andintravenous administration.

Dependence on stimulants like cocaine can occur even after usage for avery short period of time due to their potent euphoric effects. Forexample, early signs of cocaine dependence include difficulty to abstainfrom cocaine use when it is present or available. Many stimulantsincluding cocaine have a short elimination half-life and thus requirefrequent dosing to maintain the “high”. Chronic use of supratherapeuticdoses of such stimulants may result in numerous mental and/or physicalproblems. Effects on mood may include anxiety, restlessness, feelings ofsuperiority, euphoria, panic, irritation, and fearfulness. Behavioralsymptoms include but are not limited to being extremely talkative,having increased energy, stealing or borrowing money, erratic or oddbehavior, violence, lack of participation in activities that were onceenjoyable, and reckless and risky behaviors. Examples of physicalsymptoms of stimulant dependence may include one or more of thefollowing: decreased need to sleep, headaches, nosebleeds, hoarseness,increased heart rate, muscle twitches, malnutrition, increase in bodytemperature, nasal perforation, abnormal heart rhythms, chronic runnynose, constricting blood vessels, increased heart rate, increased bloodpressure, sexual dysfunction, decreased appetite, dilated pupils, risksfor contracting Human Immunodeficiency Virus (HIV), hepatitis C andother bloodborne diseases, gangrene of the bowel, cravings, and tremors.Examples of psychological symptoms of stimulant dependence may includeone or more of the following: severe paranoia, violent mood swings,break from reality, lack of motivation, psychosis, hallucinations,inability to use sound judgment, and the rationalization of drug use.There is a variety of factors that can trigger or play a role instimulant use disorder or stimulant dependence. Generally, these factorscan be placed into three categories: genetic, biological, andenvironmental. Research has shown that individuals who have relativeswith addiction problems are more likely to develop an addictionincluding cocaine dependence. The likelihood of becoming stimulantdependent is higher if the relative is a parent. Changes in brainfunction may be a biological factor that correlates with addictionproblems. For example, low dopamine levels in the brain may result in anindividual to abuse substances with the goal to attain pleasurablefeelings. Environmental factors include but are not limited tounpredictable situations in the home lives of an individual; stressors,such as child abuse, the loss of a loved one, or other traumatic events.There is a need in the art for forms of methylphenidate that have a slowgradual increase in methylphenidate blood/brain concentrations untilpeak concentrations are achieved, or a slow gradual decrease ofmethylphenidate blood/brain concentrations after peak concentrations, orboth. Not wishing to be bound by any particular theory, it is possiblethat slow onset of stimulant concentrations can decrease cardiovascularside effects, and slow elimination can decrease rebound effects. It hasalso been suggested that a larger increase in synaptic dopamine per timeunit (i.e., higher rate of dopamine increase) results in more robust andintense euphoric effect. A slow increase in methylphenidate brainconcentration produces a low rate of increase in synaptic dopamine andthus, may result in less rewarding and reinforcing effects. Withoutwishing to be bound by any particular theory, it has also been suggestedthat high occupancy of dopamine transporter receptors may decrease therewarding and reinforcing effects of additional doses of stimulants likecocaine. This could be accomplished, for example, by repeatedadministration of large doses of a form of methylphenidate with a slowonset that does not result in euphoria.

There is also a need in the art for forms of methylphenidate that canprovide a more rapid onset of methylphenidate blood/brainconcentrations. Not wishing to be bound by any theory, certainindications may require a large and fast initial spike in blood and/orbrain concentration of methylphenidate to provide to the subjectsufficient efficacy, while other indications may require lowerblood/brain concentrations of methylphenidate, but a small therapeuticamount of a form of methylphenidate with rapid onset may still bebeneficial to provide fast efficacy when needed.

There is a further need in the art for forms of methylphenidate that canprovide flexibility in dosing regimens. For example, a single daily doseform of methylphenidate in a composition that can provide both immediateand extended release PK profiles would be highly desirable.

There is an additional need in the art for forms of methylphenidate thatcan maintain the pharmacological benefit when administered, inparticular via the oral route, but which preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration.

BRIEF SUMMARY OF THE INVENTION

The present technology provides a particular d-threo-methylphenidate(“d-MPH”, “d-methylphenidate”, “dexmethylphenidate”) conjugate, orpharmaceutically acceptable salts thereof, to provide, for example, atleast one single daily dose form of a d-methylphenidate conjugate in acomposition with unconjugated methylphenidate that can provide bothimmediate and extended release PK profiles when compared to unconjugatedd-methylphenidate. The release profile in some instances provides theability of the prodrug or composition to be administered using dosingregimens that are not easily utilized with the unconjugatedd-methylphenidate. In some embodiments, the unconjugated methylphenidatein the composition can be d-methylphenidate, l-methylphenidate, or amixture thereof, and/or a therapeutic or pharmaceutically acceptablesalt thereof.

In another aspect, the present technology provides a prodrug compositioncomprising at least one conjugate of d-methylphenidate having astructure of Formula I:

and unconjugated methylphenidate, wherein the unconjugatedmethylphenidate comprises d-methylphenidate.

In another aspect, the present technology provides at least one prodrugcomposition comprising at least one conjugate, wherein the at least oneconjugate is d-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser (Formula I), orpharmaceutically acceptable salts thereof, and unconjugatedmethylphenidate.

In a further aspect, the present technology provides a compositioncomprising unconjugated methylphenidate and at least one conjugate,wherein the at least one conjugate has at least two or more chiralcenters and the composition is optically active.

In yet another aspect, the present technology provides a method forchemically synthesizing a d-methylphenidate-CO₂CH₂-nicotinoyl-L-Serconjugate of the present technology by performing the appropriate stepsto conjugate d-methylphenidate to the —CO₂CH₂-nicotinoyl-L-Ser ligand.

In further aspects, some embodiments of the compositions of the presenttechnology, comprising (a) the conjugate of Formula I and/or itspharmaceutically acceptable salt(s) and (b) unconjugated methylphenidate(comprising d-methylphenidate) and/or its pharmaceutically acceptablesalts, unexpectedly exhibit increased plasma concentrations ofd-methylphenidate after T_(max) (or later) resulting in a controlled orextended-release profile as compared to an equimolar dose of unmodifiedd-methylphenidate.

In another aspect, some embodiments of the compositions of the presenttechnology, comprising (a) the conjugate of Formula I and/or itspharmaceutically acceptable salt(s) and (b) unconjugated methylphenidate(comprising d-methylphenidate) and/or its pharmaceutically acceptablesalts, exhibit increased plasma concentrations of d-methylphenidate fromabout 0 to about 4 hours following oral administration as compared to anorally administered equimolar dose of unconjugated d-methylphenidatereleased from Concerta®.

In a further aspect, some embodiments of the compositions of the presenttechnology, comprising (a) the conjugate of Formula I and/or itspharmaceutically acceptable salt(s) and (b) unconjugated methylphenidate(comprising d-methylphenidate) and/or its pharmaceutically acceptablesalts, exhibit increased plasma concentrations of d-methylphenidate forup to about 4 hours following oral administration as compared to anorally administered equimolar dose of unconjugated d-methylphenidatereleased from Concerta®.

In yet a further aspect, some embodiments of the compositions of thepresent technology, comprising (a) the conjugate of Formula I and/or itspharmaceutically acceptable salt(s) and (b) unconjugated methylphenidateand/or its pharmaceutically acceptable salts, surprisingly exhibit lessinterpatient variability in the oral pharmacokinetic (PK) profile whencompared to unconjugated d-methylphenidate.

In yet another aspect, some embodiments of the compositions of thepresent technology are provided in an amount sufficient to provide anincreased AUC when compared to unconjugated d-methylphenidate whenadministered orally at equimolar doses.

In still further aspects, some embodiments of the compositions of thepresent technology are provided in an amount sufficient to provide asurprisingly lower C_(max) and a lower AUC but significantly increasedpartial AUCs for time periods after T_(max) (or later) of the releasedd-methylphenidate as compared to unconjugated d-methylphenidate whenadministered orally at equimolar doses.

In yet further aspects, some embodiments of the compositions of thepresent technology are provided in an amount sufficient to provide alower C_(max) and a similar AUC, but significantly increased partialAUCs for time periods after T_(max) (or later) of the releasedd-methylphenidate as compared to unconjugated d-methylphenidate whenadministered orally at equimolar doses.

In yet an alternative aspect, some embodiments of the compositions ofthe present technology are believed to provide reduced side effects ascompared to unconjugated d-methylphenidate when administered atequimolar doses, and are also contemplated in some alternative aspectsto provide reduced abuse potential as compared to unconjugatedd-methylphenidate.

In addition, some embodiments of the compositions of the presenttechnology are also believed to unexpectedly provide an amountsufficient to provide an extended T_(max) when compared to unconjugatedd-methylphenidate when administered at equimolar doses, and/or providean equivalent T_(max) when compared to unconjugated d-methylphenidatewhen administered orally at equimolar doses.

Further, some embodiments of the compositions of the present technologyare also believed to unexpectedly provide an amount sufficient toprovide a shorter T_(max) when compared to an orally administeredequimolar dose of unconjugated d-methylphenidate released fromConcerta®.

In addition, some embodiments of the compositions of the presenttechnology are also believed to unexpectedly provide an amountsufficient to provide a longer half-life (T_(1/2)) when compared to anorally administered equimolar dose of unconjugated d-methylphenidatereleased from Concerta®.

In addition, some embodiments of the compositions of the presenttechnology are also believed to unexpectedly provide an amountsufficient to provide a longer T_(1/2) compared to unconjugatedd-methylphenidate when administered orally at equimolar doses.

Moreover, the present technology provides at least one method oftreating one or more subjects (human or animal) or patients (human oranimal) having at least one disease, disorder or condition mediated bycontrolling, preventing, limiting, or inhibiting neurotransmitteruptake/re-uptake or hormone uptake/re-uptake comprising orallyadministering to one or more subjects or patients a pharmaceuticallyand/or therapeutically effective amount of a composition of the presenttechnology, comprising unconjugated methylphenidate and/or itspharmaceutically acceptable salts, and a conjugate of Formula I and/orits pharmaceutically acceptable salts.

In still yet a further aspect, the present technology provides at leastone method of treating a subject (human or animal) having at least onedisorder or condition requiring stimulation of the central nervoussystem of the subject, comprising orally administering apharmaceutically effective amount of a composition of the presenttechnology, comprising unconjugated methylphenidate and/or itspharmaceutically acceptable salts and a conjugate of Formula I and/orits pharmaceutically acceptable salts, wherein the administration treatsat least one disorder or condition requiring stimulation of the centralnervous system of the subject.

In still yet a further aspect, the present technology provides at leastone method of treating a subject (human or animal) having at least onedisorder or condition requiring stimulation of the central nervoussystem of the subject, comprising orally administering a therapeuticallyeffective amount of a composition of the present technology, comprisingunconjugated methylphenidate and/or its pharmaceutically acceptablesalts and a conjugate of Formula I and/or its pharmaceuticallyacceptable salts, wherein the administration treats at least onedisorder or condition requiring stimulation of the central nervoussystem of the subject.

In yet another aspect, the present technology provides one or moremethods of administering to a subject a composition comprising at leastone conjugate of d-methylphenidate and unconjugated methylphenidate,wherein the administration decreases the number of and/or the amount ofmetabolites produced when compared with unconjugated d-methylphenidate.In other aspects, the one or more methods of administering thecomposition of the present technology is believed to decrease theexposure of the subject to ritalinic acid when compared withunconjugated d-methylphenidate. It is desirable to minimize exposure tometabolites, such as ritalinic acid, that do not contributesignificantly to the intended therapeutic effect because of potentialside effects or toxicity that may still occur as a result of potentialsecondary pharmacological effects of the metabolite. In someembodiments, compositions of the present technology may reduce overallexposure to ritalinic acid by about 25% to about 75%.

In yet a further embodiment, the compositions of the present technologyare believed to provide an increased water solubility of thed-methylphenidate-based conjugate or prodrug compared to unconjugatedd-methylphenidate. In another embodiment, the increased water solubilityis believed to allow for the compositions to be formed into certaindosage forms at higher concentrations, dosage strengths, or higher doseloading capacities than unconjugated d-methylphenidate. In someembodiments, such dosage forms include, for example, oral thin films orstrips.

In still yet a further embodiment, the administration to a patient(human or animal) of the d-methylphenidate-based compositions comprisingd-methylphenidate conjugates and unconjugated methylphenidate arebelieved to provide a reduced interpatient variability ofd-methylphenidate plasma concentrations, and are believed to have animproved safety profile when compared to unconjugated d-methylphenidate.

In yet another alternative embodiment, the present technology providesat least one method of treating attention-deficit hyperactivity disordercomprising administering to a subject or patient a pharmaceuticallyand/or therapeutically effective amount of a composition comprising atleast one d-methylphenidate conjugate and unconjugated methylphenidate,wherein the administration treats attention-deficit hyperactivitydisorder in the subject.

In yet another alternative embodiment, the present technology providesat least one method of treating eating disorder, binge eating disorder,obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytimesleepiness (EDS), cocaine dependence, or stimulant dependence in asubject or patient comprising administering to a subject or patient apharmaceutically and/or therapeutically effective amount of acomposition comprising at least one d-methylphenidate conjugate andunconjugated methylphenidate, wherein the administration treats aneating disorder, binge eating disorder, obesity, narcolepsy, chronicfatigue, sleep disorder, excessive daytime sleepiness (EDS), cocainedependence, or stimulant dependence in a subject or patient.

In another further embodiment, the present technology provides acomposition for treating at least one subject or patient having adisorder or condition requiring stimulation of the central nervoussystem of the subject, wherein the composition comprises unconjugatedmethylphenidate and a d-methylphenidate conjugate, and wherein thecomposition has a reduced abuse potential when administered compared tounconjugated d-methylphenidate.

In a further embodiment, the compositions of the present technology arecontemplated to exhibit reduced or prevented pharmacological activitywhen administered by parenteral routes, or reduced plasma or bloodconcentration of released d-methylphenidate when administeredintranasally, intravenously, intramuscularly, subcutaneously or rectallyas compared to free unconjugated d-methylphenidate when administered atequimolar amounts.

In some embodiments, the compositions of the present technology have anextended or controlled release profile as measured by plasmaconcentrations of released d-methylphenidate when compared tounconjugated d-methylphenidate when administered orally at equimolardoses. In some embodiments, the plasma concentration ofd-methylphenidate released from the conjugate of the composition wouldincrease more slowly and over a longer period of time after oraladministration, resulting in a delay in peak plasma concentration ofreleased d-methylphenidate and in a longer duration of action whencompared to unconjugated d-methylphenidate. In further embodiments, thecontrolled release profile of d-methylphenidate of the composition wouldhave a T_(max) that is about equal to unconjugated d-methylphenidate butprovides plasma concentrations of d-methylphenidate that are sustainedfor a longer period of time as compared to unconjugatedd-methylphenidate.

In other embodiments, the composition has a lower AUC and lower C_(max),but an equivalent T_(max) and higher d-methylphenidate plasmaconcentrations in the second half of the day when administered orallyonce per day compared to unconjugated d-methylphenidate administeredorally once per day.

In another aspect, the present technology provides a pharmaceutical kitcomprising a specified amount of individual doses in a package, eachdose comprising a pharmaceutically and/or therapeutically effectiveamount of a composition comprising at least one conjugate ofd-methylphenidate and unconjugated methylphenidate. The pharmaceuticalkit also comprises instructions for use.

In another further aspect, the present technology provides an oralformulation. The oral formulation may comprise a therapeutic dose of (a)d-threo-methylphenidate (S)-serine conjugate and/or its pharmaceuticallyacceptable salts, and (b) unconjugated methylphenidate and/or itspharmaceutically acceptable salts.

In certain embodiments, compositions of the present technologycomprising unconjugated methylphenidate and at least one conjugate ofd-methylphenidate can be used in neonatal, pediatric, adolescent, adultand/or geriatric subjects with ADHD. For example, in some embodiments,the present compositions can be used for a once-daily dosing with apotentially improved onset and a long duration of action, attributesthat may benefit neonatal, pediatric and/or adolescent subjects withADHD.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Oral PK curves comparing the bioavailability of d-MPH and I-MPHwith unconjugated methylphenidate in rats.

FIG. 2. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Thrconjugate with l-MPH-CO₂CH₂-nicotinoyl-L-Thr in rats.

FIG. 3. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Serconjugate with l-MPH-CO₂CH₂-nicotinoyl-L-Ser in rats.

FIG. 4. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Ser withunconjugated d-methylphenidate in rats.

FIG. 5. Intranasal PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Serwith unconjugated d-methylphenidate in rats.

FIG. 6. Intravenous PK curves comparing thed-MPH-CO₂CH₂-nicotinoyl-L-Ser with unconjugated d-methylphenidate inrats.

FIG. 7. Oral PK curve of the mean (N=24) plasma concentration-timeprofiles of intact d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser aftera single oral dose of 32 mg of the composition comprisingd-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser.

FIG. 8. Oral PK curves of the mean (N=12) d-methylphenidate plasmaconcentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg,and following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg(steady state) administered in adult human subjects once every 24 hours

FIG. 9. Oral PK curves of the mean (N=12) d-methylphenidate plasmaconcentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg,and following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg(steady state) administered in adult human subjects once every 24 hours.

FIG. 10. Oral PK curves of the mean (N=10) d-methylphenidate plasmaconcentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg,and following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg(steady state) administered in adult human subjects once every 24 hours,calculated without the outlier subjects (N=2).

FIG. 11. Oral PK curves showing the mean d-methylphenidate plasmaconcentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgin adult human subjects, calculated with and without the outliersubjects.

FIG. 12. Oral PK curves showing mean d-methylphenidate plasmaconcentration-time profile following the 7^(th) dose after multiple oraldoses of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride,12/56 mg administered in adult human subjects once every 24 hours,calculated with and without the outlier subjects.

FIG. 13. Oral PK curves of the mean (N=12) d-methylphenidate plasmaconcentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg,and following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg(steady state) administered in adult human subjects once every 24 hours.

FIG. 14. Oral PK curves of the mean (N=12) d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mgand following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mgadministered in adult human subjects once every 24 hours.

FIG. 15. Oral PK curves of the mean (N=12) d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mgadministered in adult human subjects once every 24 hours.

FIG. 16. Oral PK curves of the mean (N=12) d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgand following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgadministered in adult human subjects once every 24 hours.

FIG. 17. Oral PK curves showing the mean d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgand following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgadministered in adult human subjects once every 24 hours calculatedwithout the outlier subjects.

FIG. 18. Oral PK curves showing the mean d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgin adult human subjects calculated with and without the outliersubjects.

FIG. 19. Oral PK curves showing the mean d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following the 7^(th) dose aftermultiple oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg administered inadult human subjects once every 24 hours calculated with and without theoutlier subjects.

FIG. 20. Oral PK curves of the mean d-MPH-CO₂CH₂-nicotinoyl-L-Ser plasmaconcentration-time profile following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg administered inadult human subjects once every 24 hours.

FIG. 21. Oral PK curves showing the mean d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mgadministered in adult human subjects once every 24 hours calculated withand without outlier subjects.

FIG. 22. Oral PK curves of the mean (N=12) d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mgand following the 7^(th) dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mgadministered in adult human subjects once every 24 hours.

FIG. 23. Oral PK curves of the mean (N=12) d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mgadministered in adult human subjects once every 24 hours.

FIG. 24. Oral PK curves showing the mean d-MPH-CO₂CH₂-nicotinoyl-L-Serplasma concentration-time profile following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg,d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg,and d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48mg, in adult human subjects.

FIG. 25. Oral PK curves showing the mean (N=12)d-MPH-CO₂CH₂-nicotinoyl-L-Ser plasma concentration-time profilefollowing the 7^(th) dose after multiple oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg, d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg, andd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg,administered in adult human subjects once every 24 hours.

FIG. 26. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg,and Concerta®, 54 mg, in adult human subjects.

FIG. 27. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following the 7th dose after multiple oraldoses of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride,8/64 mg, and Concerta®, 54 mg, administered in adult human subjects onceevery 24 hours.

FIG. 28. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg, and Concerta®, 54mg, taken once every 24 hours for 7 days in adult human subjects.

FIG. 29. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg,and Concerta®, 54 mg, in adult human subjects.

FIG. 30. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following the 7th dose after multiple oraldoses of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride,12/56 mg, and Concerta®, 54 mg, administered in adult human subjectsonce every 24 hours.

FIG. 31. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg, and Concerta®, 54mg, taken once every 24 hours for 7 days in adult human subjects.

FIG. 32. Oral PK curves showing the mean d-methylphenidate plasmaconcentration-time profile following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg, administered inadult human subjects once every 24 hours calculated with and withoutoutlier subjects.

FIG. 33. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg,and Concerta®, 54 mg, in adult human subjects.

FIG. 34. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following the 7th oral dose after multipleoral doses of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Serchloride, 16/48 mg, and Concerta®, 54 mg, administered in adult humansubjects once every 24 hours.

FIG. 35. Oral PK curves showing d-methylphenidate plasmaconcentration-time profiles following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg, and Concerta®, 54mg, taken once every 24 hours for 7 days in adult human subjects.

DETAILED DESCRIPTION OF THE INVENTION

The present technology provides one or more compositions comprising (a)unconjugated methylphenidate and (b) d-methylphenidate conjugated to anicotinoyl-L-serine moiety to form a prodrug. The composition hassurprising beneficial properties as further described herein.

The use of the term “methylphenidate” herein is meant to include any ofthe stereoisomer forms of methylphenidate, including the fourstereoisomers: d-erythro-methylphenidate, l-erythro-methylphenidate,d-threo-methylphenidate and l-threo-methylphenidate and the salts andderivatives thereof. Methylphenidate is interchangeable with methylphenyl(piperidin-2-yl)acetate. The term “methylphenidate” includes allsalt forms. Methylphenidate is also known by its trade name Concerta®(commercially available from Janssen Pharmaceuticals, Inc., Beerse,Belgium), Ritalin®, Ritalin® SR, Methylin®, Methylin® ER (allcommercially available from Novartis International AG, of Basil,Switzerland). The methylphenidate used in the present technology can beany stereoisomer of methylphenidate, including, but not limited to,d-erythro-methylphenidate, l-erythro-methylphenidate,d-threo-methylphenidate and l-threo-methylphenidate. In a preferredembodiment, the conjugates contain a single d-threo-methylphenidateisomer. In another embodiment, the prodrug conjugates are opticallyactive single isomers thereof.

The use of the term “unconjugated methylphenidate” means methyl2-phenyl-2-(piperidin-2-yl)acetate and salts thereof.

Stereoisomers, used hereinafter, means that two molecules are describedas stereoisomers of each other if they are made of the same atoms,connected in the same sequence, but the atoms are positioned differentlyin space. The difference between two stereoisomers can only be seen whenthe three-dimensional arrangement of the molecules is considered.

Bioavailability, used hereinafter, means the proportion of a drug orother substance that enters the circulation over time when introducedinto the body and so is able to have an active effect.

C_(max), used hereinafter, is a term used in pharmacokinetics and refersto the maximum (or peak) plasma concentration that a drug achieves in aspecified compartment or test area of the body after the drug has beenadministered and before the administration of a second dose.

T_(max), used hereinafter, is the term used in pharmacokinetics todescribe the time at which the C_(max) is observed. After an intravenousadministration, C_(max) and T_(max) are closely dependent on theexperimental protocol, since the concentrations are always decreasingafter the dose.

As known to those skilled in the art, the term “Steady State” means thestate in which the overall intake of a drug is in approximate dynamicequilibrium with its elimination. At steady state, total drug exposuredoes not change significantly between successive dosing periods. Steadystate is typically achieved following a time period about 4-5 times thehalf-life of a drug after regular dosing was started.

The use of the term “dose” means the total amount of a drug or activecomponent taken each time by an individual subject.

As used herein, the term “subject” means a human or animal, includingbut not limited to a human or animal patient.

The term “patient” means a human or animal subject in need of treatment.

The use of the term “interpatient variability” means an estimate of thelevels of pharmacokinetic variability between different individualsreceiving the same dose of the same drug. The estimate can be made, forexample, by calculating the coefficient of variation (CV) of certainpharmacokinetics parameters including, for example, C_(max), AUC_(last),AUC_(inf), and T_(max). When comparing interpatient variability betweendifferent drugs or between the same drug(s) in different formulations,lower CV indicates reduced interpatient variability and higher CVindicates increased interpatient variability.

“Coefficient of variant” (CV) is a term used in statistics and iscalculated based on the following formula: CV=standarddeviation/mean*100.

AUC_(last) is a term used in pharmacokinetics to describe the area underthe curve in a plot of drug concentration in blood, serum, or plasma vstime from time=0 (or predose) to the time of the last measurable drugconcentration.

AUC_(inf) is a term used in pharmacokinetics to describe the area underthe curve in a plot of drug concentration in blood, serum, or plasma vstime from time=0 (or predose) to infinity.

Molar equivalent as used hereinafter, means an equal number of moles ofthe substance as the number of moles in a certain mass (weight) orvolume, e.g. a dose of d-methylphenidate that is molar equivalent to adose of about 0.1 mg d-methylphenidate hydrochloride per day wouldprovide the same number of moles of d-methylphenidate as from 0.1 mg ofd-methylphenidate hydrochloride.

As used herein, the phrases such as “decreased,” “reduced,” “diminished”or “lowered” are meant to include at least about a 10% change inpharmacological activity, area under the curve (AUC) and/or peak plasmaconcentration (C_(max)) with greater percentage changes being preferredfor reduction in abuse potential and overdose potential of theconjugates of the present technology as compared to unconjugatedmethylphenidate. For instance, the change may also be greater than about10%, about 15%, about 20%, about 25%, about 35%, about 45%, about 55%,about 65%, about 75%, about 85%, about 95%, about 96%, about 97%, about98%, about 99%, or increments therein.

“Pharmaceutically effective amount” as used herein means an amount thathas a pharmacological effect. A “pharmaceutically acceptable salt” asused herein is a salt of the d-methylphenidate conjugate or unconjugatedmethylphenidate or both which, when used in a pharmaceutically effectiveamount, has at least one pharmacological effect.

“Therapeutically effective amount” as used herein means an amounteffective for treating a disease or condition. A “therapeuticallyacceptable salt” as used herein is a pharmaceutically acceptable salt ofthe d-methylphenidate conjugate or unconjugated methylphenidate or bothin the composition of the present technology, which, when used in atherapeutically effective amount, is effective for treating a disease,condition, or syndrome.

As used herein, the term “attention deficit hyperactivity disorder”(ADHD) encompasses various sub-types of ADHD including, for example,subjects who do not show or only show weak symptoms of hyperactivity orimpulsiveness, or for example, subjects who are predominatelyinattentive (formerly attention deficit disorder (ADD)).

As used herein, the term “prodrug” refers to a substance that isinactive or has reduced pharmacological activity but is converted to anactive drug by a chemical or biological reaction in the body. In thepresent technology, the prodrug is a conjugate of at least one drug,d-methylphenidate, a linker, and a nicotinoyl-L-serine moiety. Thus, theconjugates of the present technology are prodrugs and the prodrugs ofthe present technology are conjugates.

Prodrugs are often useful because, in some embodiments, they may beeasier to administer or process than the parent drug. They may, forinstance, be more bioavailable by oral administration whereas the parentdrug is not. The prodrug may also have improved solubility in waterand/or other solvents over the parent drug. An embodiment of a prodrugwould be a d-methylphenidate conjugate that is metabolized to the activemoiety. In certain embodiments, upon in vivo administration, a prodrugis chemically converted to the biologically, pharmaceutically ortherapeutically more active form of the compound. In certainembodiments, a prodrug is enzymatically metabolized by one or more stepsor processes to the biologically, pharmaceutically or therapeuticallyactive form of the compound. To produce a prodrug, a pharmaceuticallyactive compound is modified such that the active compound will beregenerated upon in vivo administration. The prodrug is designed toalter the metabolism or the transport characteristics of a drug—thechanges typically varying with route of administration—in certainembodiments, to mask side-effects or toxicity, to improvebioavailability and/or water solubility, to improve the flavor of a drugor to alter other characteristics or properties of a drug in otherdiscrete embodiments.

The d-methylphenidate prodrug can be prepared so as to have a variety ofdifferent chemical forms including chemical derivatives or salts. Suchd-methylphenidate prodrugs can also be prepared to have differentphysical forms. For example, the d-methylphenidate prodrug may beamorphous, may have different crystalline polymorphs, or may exist indifferent solvation or hydration states, such as semi-hydrates,monohydrates, hydrates (nH₂O, when n is 0.5, 1, 2 . . . ). Suchpolymorphs can be produced by, e.g., using crystallization conditions toisolate a free-base and salt forms and/or by ball-milling such forms.

By varying the form of the d-methylphenidate prodrug, it is possible tovary the physical properties thereof. For example, crystallinepolymorphs typically have different solubilities from one another, suchthat a more thermodynamically stable polymorph is less soluble than aless thermodynamically stable polymorph. Pharmaceutical polymorphs canalso differ in properties such as shelf-life, bioavailability,morphology, vapor pressure, density, color, and compressibility.Accordingly, variation of the crystalline state of the d-methylphenidateprodrug is one of many ways in which to modulate the physical propertiesthereof.

A co-crystal is a multiple component crystal containing two or morenon-identical molecules in which all components are solid under ambientconditions (i.e., 22° Celsius, 1 atmosphere of pressure) when in theirpure form. The components comprise a target molecule (i.e., ad-methylphenidate prodrug) and a molecular co-crystal former thatcoexist in the co-crystal at the molecular level within a singlecrystal.

Co-crystals that comprise two or more molecules (co-crystal formers)Jmarsson et al., 2004) that are solids under ambient conditionsrepresent a long-known class of compounds (see Wohler, 1844). However,co-crystals remain relatively unexplored. A Cambridge StructuralDatabase (CSD) (Allen et al., 1993) survey reveals that co-crystalsrepresent less than 0.5% of published crystal structures. Nevertheless,their potential impact upon pharmaceutical (e.g., nutraceutical)formulation (Vishweshwar et al., 2006; Li et al., 2006; Remenar et al.,2003; and Childs et al., 2004) and green chemistry (Anastas et al.,1998) is of topical and growing interest. In particular, the fact thatall co-crystal components are solids under ambient conditions hasimportant practical considerations because synthesis of co-crystals canbe achieved via solid-state techniques (mechanochemistry) (Shan et al.,2002), and chemists can execute a degree of control over the compositionof a co-crystal since they can invoke molecular recognition, especiallyhydrogen bonding, during the selection of co-crystal formation. Thosefeatures distinguish co-crystals from solvates which are another broadand well-known group of multiple component compounds. Solvates are muchmore widely characterized than co-crystals (e.g., 1652 co-crystals arereported in the CSD versus 10,575 solvates; version 5.27 (May 2006) 3Dcoordinates, RO.075, no ions, organics only).

It would be advantageous to have new forms of d-methylphenidate prodrugsthat have improved properties. Specifically, it is desirable to identifyimproved forms of d-methylphenidate prodrugs that exhibit significantlyimproved properties including increased aqueous and/or solventsolubility and stability. Further, it is desirable to improve theprocessability, or preparation of pharmaceutical formulations. Forexample, needle-like crystal forms or habits of d-methylphenidateprodrug can cause aggregation, even in compositions where thed-methylphenidate prodrug is mixed with other substances, such that anon-uniform mixture is obtained. It is also desirable to increase ordecrease the solution rate of d-methylphenidate prodrug-containingpharmaceutical compositions in water or other solvents, increase ordecrease the bioavailability of orally-administered compositions, andprovide a more rapid or more delayed onset to therapeutic effect. It isalso desirable to have a form of the d-methylphenidate prodrug which,when administered to a subject, reaches a peak plasma level faster orslower, has a longer lasting therapeutic plasma concentration, andhigher or lower overall exposure when compared to equivalent amounts ofthe d-methylphenidate prodrug in its presently-known form. The improvedproperties discussed above can be altered in a way which is mostbeneficial to a specific d-methylphenidate prodrug for a specifictherapeutic effect.

The d-methylphenidate prodrug or conjugate of the present technology andthe unconjugated methylphenidate can be either a positively charged(cationic) molecule, or a pharmaceutically acceptable anionic orcationic salt form or salt mixtures with any ratio between positive andnegative components. These anionic salt forms can include, but are notlimited to, for example, acetate, l-aspartate, besylate, bicarbonate,carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate,fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride,d-lactate, i-lactate, d,l-lactate, d,l-malate, l-malate, mesylate,pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate,l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate,d-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate,borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate,cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate,fusidate, galactarate, galacturonate, gallate, gentisate, glutamate,glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, orundecylenate. In the preferred embodiments, the anionic salt form isselected from the group consisting of chloride, hydrogen carbonate(bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate,hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite(bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate,bromate, iodate, chlorate, fluoride, nitrite.

In some embodiments, the salt form of the conjugate is selected from thegroup consisting of chloride, hydrogen carbonate (bicarbonate), iodide,bromide, citrate, acetate, formate, salicylate, hydrogen sulfate(bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite),propionate, benzene sulfonate, hypophosphite, phosphate, bromate,iodate, chlorate, fluoride, and nitrite. In some embodiments, the saltform of the unconjugated methylphenidate is selected from the groupconsisting hydrochloride, hydrobromide, hydroiodide, formate, mesylate,tartrate, salicylate, sulfate, citrate, nitrate, hydrogen sulfite,propionate, benzene sulfonate, and acetate.

The cationic salt forms can include, but are not limited to, forexample, sodium, potassium, calcium, magnesium, lithium, cholinate,lysinium, or ammonium.

Without wishing to be limited to the following theory, it is believedthat the prodrugs/conjugates of the present technology undergo ratedetermining enzyme hydrolysis in vivo, which subsequently leads to acascade reaction resulting in rapid formation of d-methylphenidate andthe respective ligands, metabolites thereof and/or derivatives thereof.The prodrug conjugates of the present technology are non-toxic or havevery low toxicity at the given dose levels and are preferably knowndrugs, natural products, metabolites, or GRAS (Generally Recognized AsSafe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxicmimetics or derivatives thereof.

General Structures and Definitions

Abbreviations for the components of the compositions of the presenttechnology include: MPH stands for methylphenidate; MPH.HCl stands formethylphenidate hydrochloride; Ser stands for serine; Thr stands forthreonine; ^(t)Bu stands for tert-butyl; Et stands for ethyl.

In some embodiments, the general structure of the prodrugs ofd-methylphenidate of the present technology can be represented byFormula I:

In some embodiments, the conjugate has at least two or more chiralcenters. In some embodiments the conjugate has three chiral centers,such as the three chiral centers shown in Formula I.

In one embodiment, the conjugate can be an ionic salt, such as chloride,preferably d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, having the followingFormula II:

In preferred embodiments of the compositions of the present technology,the d-methylphenidate active is derived from two sources, thed-methylphenidate prodrug or conjugate and/or its pharmaceuticallyacceptable salts, and unconjugated methylphenidate and/or itspharmaceutically acceptable salts. In some alternative embodiments,additional sources can contribute to the d-methylphenidate active,including but not limited to, other conjugates, non-conjugatedmethylphenidate, methylphenidate-like stimulants, amphetamines, andamphetamine-like stimulants. The amount of d-methylphenidate active thateach source contributes can vary from about 5% to about 95% by weight,based on the total weight of the d-methylphenidate active, including,but not limited to, amounts of about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, or anyamounts in between, in increments of about 0.5%, about 1%, about 2.5%,or about 5%. In some embodiments, the d-methylphenidate conjugatecontributes an amount of d-methylphenidate active that is about 60% byweight, alternatively about 70%, alternatively about 75%, alternativelyabout 80%, alternatively about 85%, alternatively about 90%,alternatively about 95% by weight, of the total d-methylphenidateactive, or any amounts in between, in increments of about 0.5%, about1%, about 2%, about 2.5%, or 5%; and the unconjugated methylphenidatecontributes about 40% by weight, alternatively about 30%, alternativelyabout 25%, alternatively about 20%, alternatively about 15%,alternatively about 10%, alternatively about 5% by weight of the totald-methylphenidate active, or any amounts in between, in increments ofabout 0.5%, about 1%, about 2%, about 2.5%, or 5%.

It should be appreciated that the weight percentages recited above forthe d-methylphenidate conjugate are expressed in terms of the totalweight of the d-methylphenidate active in the composition and not thetotal weight of the d-methylphenidate conjugate. In some embodiments,the combination of the unconjugated methylphenidate andd-methylphenidate conjugate in the composition can be expressed in thefollowing format: “weight of the unconjugated d-methylphenidateactive/weight of the d-methylphenidate conjugate”. In some specificembodiments described herein, the combination of the unconjugatedd-methylphenidate active and d-methylphenidate conjugate is expressed as8/64 mg, 12/56 mg, and 16/48 mg, where the first number (8, 12, 16)refers to the weight of the unconjugated d-methylphenidate hydrochlorideactive in mg, and the second number (64, 56, 48) refers to the weight ofthe chloride salt of the d-methylphenidate conjugate,d-MPH-CO₂—CH₂-nicotinoyl-L-Ser chloride, in mg. (See Table 11). Theamount of conjugate in these embodiments is the molar equivalent to 32mg, 28 mg and 24 mg of d-methylphenidate hydrochloride, respectively,making the molar weight ratios of unconjugated d-methylphenidate andd-methylphenidate conjugate 20%/80%, 30%/70%, and 40%/60%, respectively,based on a total molar equivalent amount of d-methylphenidatehydrochloride of 40 mg.

Administration, Formulation and Advantages

The compositions of the present technology, comprising d-methylphenidateprodrugs or conjugates and unconjugated methylphenidate, can beadministered, for example, orally or rectally, and, upon administration,release the active d-methylphenidate, derivatives thereof orcombinations thereof, after being hydrolyzed in the body. Not wishing tobe bound by any particular theory, the nicotinoyl-L-serine ligand thatis conjugated to the d-methylphenidate of the present technologycomprises niacin and serine, both naturally occurring metabolites,pharmaceutically active compounds or mimetics thereof or derivativesthereof. It is believed that the prodrugs or conjugates of the presenttechnology can be easily recognized by physiological systems resultingin hydrolysis and release of d-methylphenidate.

The prodrugs of the present technology are believed to have no orlimited pharmacological activity themselves and consequently may followa metabolic pathway that differs from the parent drug (i.e.,methylphenidate).

It has been surprisingly found that in some embodiments of the presenttechnology, the compositions comprising prodrugs or conjugates ofd-methylphenidate and unconjugated methylphenidate provide acontrolled-release or extended-release profile as compared withunconjugated d-methylphenidate. In some embodiments, the prodrugs orconjugates of the present technology surprisingly provide increasedwater solubility as compared with unconjugated d-methylphenidate. Insome embodiments, the prodrugs or conjugates of the present technologyhave at least about 1.2 times or at least about 1.5 times the watersolubility of unconjugated d-methylphenidate. In some embodiments, theprodrugs or compositions of the present technology have at least about1.7, at least about 2.0, at least about 2.2, at least about 2.5, atleast about 3.0, at least about 4.0 or at least about 5 times the watersolubility of unconjugated d-methylphenidate, and include any multiplesin between or above that have water solubility greater than unconjugatedd-methylphenidate. Not to be bound by any particular theory, theincrease in water solubility may allow for the conjugate to be formedinto certain dosage forms at higher concentrations, dosage strengths orhigher dose loading capacities than unconjugated d-methylphenidate. Insome embodiments, these dosage forms include, but are not limited to,forms that require water solubility, including, but not limited to,liquids and/or oral thin films or strips.

In some embodiments, the composition of the present technology,comprising (a) the prodrug or conjugate and/or its pharmaceuticallyacceptable salts, and (b) unconjugated methylphenidate and/or itspharmaceutically acceptable salts, is also believed to unexpectedlyexhibit both immediate-release (during the time period before T_(max))and extended-release (during the time period after T_(max)) PK profilesas a single daily dosage form when compared to unmodifiedd-methylphenidate. Further, it is believed that the conjugate is capableof being enzymatically or hydrolytically activated or converted into theactive form. Further, the composition described herein is believed torelease d-methylphenidate, its active metabolites and/or derivatives andtheir combination, resulting in improved PK profile outcome and/orexposure to d-methylphenidate, its active metabolites and/or derivativeswhen compared to free or unconjugated d-methylphenidate at equimolardoses. In some embodiments, the composition of the present technology,comprising the prodrug and/or its pharmaceutically acceptable salts andunconjugated methylphenidate and/or its pharmaceutically acceptablesalts, provides plasma concentrations of d-methylphenidate released fromthe composition that are increased from about 0 to about 1 hourfollowing oral administration in a human subject when compared tounconjugated d-methylphenidate released from Concerta®. In otherembodiments, plasma concentrations of d-methylphenidate released fromthe composition are increased from 0 to about 2 hours, 0 to about 3hours, 0 to about 4 hours, or 0 to about 0.5 hours, following oraladministration of a human subject. Time 0 hours as used herein refers tothe time of administration.

Not to be bound by any particular theory, it is believed that this mayallow for administration of a lower dose with equal or improvedtherapeutic effect, but with fewer and/or less severe side effects whencompared to unmodified d-methylphenidate, thereby improving the safetyprofile of the drug, yet while achieving patient therapeutic efficacy.Common side effects of d-methylphenidate are nervousness, agitation,anxiety, and insomnia or drowsiness. Other common side effects areabdominal pain, weight loss, hypersensitivity, nausea, dizziness,palpitation, headache, dyskinesia, blood pressure, pulse changes,tachycardia, angina, and cardiac arrhythmia.

In one embodiment, the compositions comprising the at least one prodrugor conjugate of the present technology would alter the metabolic profileof d-methylphenidate, derivatives thereof or combinations thereof, by,for example, changing the amounts and/or ratio of d-methylphenidate andits metabolites, such as the inactive ritalinic acid within the body.The prodrug or conjugate of the present technology, for example, woulddecrease the number and/or the amount of metabolites, including active,inactive, toxic or non-toxic metabolites, produced by unconjugatedd-methylphenidate. Not wishing to be bound by any particular theory, itis believed that this change in metabolism may potentially alleviatecertain side effects of any metabolite(s), as well as potentiallyimprove upon the safety profile of d-methylphenidate. In someembodiments, compositions of the present technology may reduce theoverall exposure to ritalinic acid by about 25% up to about 75% ascompared to the amount of ritalinic acid produced by an equimolar amountof unconjugated d-methlyphenidate. In some embodiments, the overallexposure to ritalinic acid may be reduced by about 30%, alternativelyabout 35%, alternatively about 40%, alternatively about 45%,alternatively about 50%, alternatively about 55%, alternatively about60%, alternatively about 65%, alternatively about 70% as compared to anequimolar amount of unconjugated d-methlyphenidate.

In another embodiment, the compositions comprising the prodrugs orconjugates of the present technology and unconjugated methylphenidatewould unexpectedly produce reduced interpatient variability ofd-methylphenidate plasma concentrations. Not to be bound by anyparticular theory, it can be assumed that the reduction of interpatientvariability of d-methylphenidate plasma concentrations may be due toeither increased bioavailability or a modified metabolic pathway or acombination of both. In another embodiment, the compositions comprisingthe prodrug of the present technology and unconjugated methylphenidatewould alter the metabolic pathway of the released d-methylphenidate whencompared to unmodified d-methylphenidate. It is believed that in such anembodiment, the metabolism of the prodrug may decrease interpatientvariability and/or reduce side effects associated with unconjugatedd-methylphenidate or any of its metabolites.

In a further embodiment, the at least one prodrug or conjugate of thepresent technology can comprise racemic d- and l-methylphenidate whichis preferably hydrolyzed to d-methylphenidate in the body and thusdelivers more of the therapeutically active d-isomer. Wishing not to bebound by any particular theory, this may reduce potential side effectscaused by l-methylphenidate and/or its metabolites.

In some embodiments, the compositions of the present technology arebelieved to exhibit an improved immediate-release and/orextended-release PK profile, compared to unconjugated d-methylphenidatewhen administered orally at equimolar doses. In some embodiments, thecompositions of the present technology are believed to surprisinglygenerate both a C_(max) and an AUC value of released d-methylphenidatethat exhibits an improved immediate-release or extended-release PKprofile, as a single daily dosage form, when compared to unconjugatedd-methylphenidate of Concerta® when administered orally at equimolardoses.

In some embodiments, the compositions of the present technology arebelieved to unexpectedly generate a T_(max) value of releasedd-methylphenidate that is longer than the T_(max) value produced byunconjugated d-methylphenidate when administered orally at equimolardoses.

In some embodiments, the AUC is about 50% (or smaller) of the AUC ofunconjugated d-methylphenidate, when administered intranasally orintravenously at equimolar doses, for example about 50% to about 0.1%,alternatively from about 25% to about 0.1%, alternatively from about 50%to about 1%, including, but not limited to, about 50%, about 40%, about30%, about 20%, about 10%, about 1% or any amounts in between, inincrements of about 0.5%, about 1%, about 2%, about 2.5%, about 5% orabout 10%.

D-Methylphenidate has rewarding properties and is prone to substanceabuse because of its pharmacological similarity to cocaine andamphetamine. Oral abuse has been reported to lead to hallucinations,paranoia, euphoria, and delusional disorder. Oral abuse may subsequentlyescalate to intravenous and intranasal abuse. Euphoria has been reportedafter intravenous administration of d-methylphenidate. When administeredintranasally the effect is found to be similar to intranasal use ofamphetamines.

The compounds, prodrugs, compositions and/or methods of the presenttechnology are believed to provide reduced potential for overdose,reduced potential for abuse and/or improve the characteristics ofd-methylphenidate, derivatives thereof or combinations thereof withregard to toxicities or suboptimal release profiles. The prodrugs of thepresent technology may preferably have no or a substantially decreasedpharmacological activity when administered through injection orintranasal routes of administration. However, they remain orallybioavailable. Without wishing to be limited to the below theory, it isbelieved that overdose protection may occur due to the conjugates beingexposed to different enzymes and/or metabolic pathways after oraladministration whereby the conjugate of the present technology isexposed to the gut and first-pass metabolism as opposed to exposure toenzymes in the circulation or mucosal membranes in the nose, whichlimits the ability of the d-methylphenidate, derivatives thereof orcombinations thereof, from being released from the conjugate. Therefore,abuse resistance is provided by limiting the effectiveness ofalternative routes of administration. Again, not wishing to be bound byany particular theory, the route-specific bioavailability can be aresult of differential hydrolysis of the chemical linkage (i.e., acovalent linkage) following oral, intranasal, or intravenousadministration. The prodrugs of the present technology are envisioned tonot hydrolyze or to hydrolyze at a reduced rate or to a limited extentvia non-oral routes. As a result, they are believed to not generate highplasma or blood concentrations of released d-methylphenidate wheninjected or snorted compared to free d-methylphenidate administeredthrough these routes.

It is contemplated that the prodrugs of the present technology areresistant to abuse by parenteral routes of administration, such asintravenous “shooting,” or intranasal “snorting,” that are oftenemployed during illicit use. For example, release of d-methylphenidate,derivatives thereof or combinations thereof, is reduced when thecomposition of the present technology is delivered by parenteral routes.Further, the conjugates of the present technology, since they arebelieved to include covalently bound d-methylphenidate, derivativesthereof or combinations thereof, are not able to be physicallymanipulated to release the d-methylphenidate, derivatives thereof orcombinations thereof, from the conjugated d-methylphenidate, derivativesthereof or combinations thereof, by methods, for example, of grinding upor crushing of solid forms. The conjugates of the present technology arealso contemplated to exhibit resistance to chemical hydrolysis underconditions a potential drug abuser may apply to “extract” the activeportion of the molecule, for example, by boiling, or acidic or basicsolution treatment of the conjugate. Some compositions containingprodrugs or conjugates of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable.

For example, the prodrug or conjugate of the present technology iscontemplated to surprisingly maintain its effectiveness and abuseresistance following the crushing of the tablet, capsule or other oraldosage form utilized to deliver the therapeutic component (i.e., activeingredient/drug) which is believed to be due to the inherent releaseprofile being a property of the composition not formulation. Incontrast, conventional extended release formulations used to control therelease of d-methylphenidate are subject to release of up to the entired-methylphenidate content immediately following crushing. When thecontent of the crushed tablet is injected or snorted, the large dose ofd-methylphenidate produces the “rush” effect sought by addicts. In someembodiments, the compositions of the present technology potentiallyreduce drug liking. Without being bound by theory, since some of thed-methylphenidate is covalently bound in the conjugate, there is aslower of release of d-methylphenidate compared to an equimolar dose ofunconjugated d-methylphenidate, which could lead to a reduced drugliking outcome.

The present technology provides a stimulant based treatment modality anddosage form for certain disorders requiring the stimulation of the CNSsuch as, attention-deficit hyperactivity disorder (ADHD), attentiondeficit disorder (ADD)(technically ADHD, Predominantly InattentiveType), autistic spectrum disorder, autism, Asperger's disorder,pervasive developmental disorder, sleep disorder, obesity, depression,bipolar disorder, eating disorder, binge eating disorder, chronicfatigue syndrome, schizophrenia, major depressive disorder, narcolepsy,excessive daytime sleepiness (EDS), cocaine dependence, stimulantdependence, or autistic spectrum disorder. In a preferred embodiment,the at least one prodrug or composition of the present technology isused to treat attention-deficit hyperactivity disorder (ADHD).

In some embodiments, the compositions of the present technologycomprising at least one prodrug or conjugate of d-methylphenidate andunconjugated methylphenidate can be used in one or more methods oftreating a subject or patient (human or animal, preferably mammal)having at least one disease, disorder or condition requiring stimulationof the central nervous system of one or more subjects, comprising orallyadministering a pharmaceutically and/or therapeutically effective amountof the at least one composition.

In some embodiments, the composition of the present technology can beused in one or more methods of treating one or more subjects or patients(human or animal, preferably mammal) having at least one disease,disorder or condition mediated by controlling, preventing, limiting, orinhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptakecomprising administering to at least one subject a pharmaceuticallyand/or therapeutically effective amount of the composition. In someembodiments, the neurotransmitter is serotonin, dopamine ornorepinephrine. In some embodiments, the hormone is catecholamine.

At least some compositions of the present technology comprising (a) theprodrugs of methylphenidate, and/or their pharmaceutically acceptablesalts and (b) unconjugated methylphenidate and/or its pharmaceuticallyacceptable salts, can also be used for treating stimulant (cocaine,methamphetamine, among others) abuse and addiction, for improving battlefield alertness, and/or for combating fatigue.

The compositions of the present technology can be formulated into dosageforms that include but are not limited to sublingual, gummy, chewabletablet, rapidly dissolving tablet, tablet, capsule, caplet, troche,lozenge, powder, suspension, syrup, solution, oral thin film (OTF), oralstrip, rectal film, or suppository. In some embodiments, the dosageforms are to be administered orally. Preferred oral administration formsare capsule, tablet, solutions and OTF. Suitable dosing vehicles of thepresent technology include, but are not limited to, water, phosphatebuffered saline (PBS), 10% Tween in water, and 50% PEG-400 in water.

Solid dosage forms can optionally include one or more of the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,gel forming agents, fillers, flavors and colors, glidants, lubricants,preservatives, sorbents and sweeteners.

Oral formulations of the present technology can also be included in asolution, a suspension or a slurry in an aqueous liquid or a non-aqueousliquid. The formulation can be an emulsion, such as an oil-in-waterliquid emulsion or a water-in-oil liquid emulsion. The oils can beadministered by adding the purified and sterilized liquids to a preparedenteral formula, which is then placed in the feeding tube of a subjectwho is unable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations with excipients designed to form a relatively soft,flavored, tablet dosage form that is intended to be chewed rather thanswallowed. Conventional tablet machinery and procedures, for example,direct compression and granulation, i.e., or slugging, beforecompression, can be utilized. Those individuals involved inpharmaceutical solid dosage form production are versed in the processesand the machinery used, as the chewable dosage form is a very commondosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing theformulation with one or more excipients intended to add bindingqualities to disintegration qualities. The mixture is either directlycompressed or granulated and then compressed using methods and machineryknown to those in the industry. The resultant compressed tablet dosageunits are then packaged according to market need, for example, in unitdose, rolls, bulk bottles, blister packs, etc.

The present technology contemplates that the compositions of the presenttechnology can be formulated into formulations or co-formulations thatmay further comprise one or more additional components. For example,such formulations can include biologically-acceptable carriers which maybe prepared from a wide range of materials. Without being limited to,such materials include diluents, binders and adhesives, lubricants, gelforming agents, plasticizers, disintegrants, colorants, bulkingsubstances, surfactants, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated formulation or co-formulation. In one embodiment,the composition of the present technology comprises from about 10% toabout 60% by weight d-methylphenidate conjugate, or a salt thereof, fromabout 2% to about 15% by weight unconjugated d-methylphenidate, or asalt thereof, and one or more additional components to total 100% byweight, based on the total weight of the formulation. The one or moreadditional components may include, but are not limited to, diluents,lubricants, disintegrants, fillers, and glidants.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents, such as flavoring agents, preservatives, andantioxidants, among others. Such antioxidants would be food acceptableand could include, for example, vitamin E, carotene, BHT or otherantioxidants. Suitable flavoring agents and preservatives are known toone of skill in the art.

Other compounds which may be included by admixture are, for example,medically inert ingredients, e.g., solid and liquid diluents, such aslactose, dextrose, saccharose, cellulose, starch or calcium phosphatefor tablets or capsules, olive oil or ethyl oleate for soft capsules andwater or vegetable oil for suspensions or emulsions; lubricating agentssuch as silica, talc, stearic acid, magnesium or calcium stearate,hydrogenated oils, sodium stearyl fumarate, and/or polyethylene glycols;gelling agents such as colloidal clays, polyethylene oxide,hydroxypropyl methyl cellulose, or carbomers; thickening agents such asgum tragacanth or sodium alginate, binding agents such as starches,arabic gums, gelatin, methylcellulose, carboxymethylcellulose orpolyvinylpyrrolidone (povidone); disintegrating agents such as starch,alginic acid, alginates, crospovidone, or sodium starch glycolate;effervescing mixtures; dyestuff; sweeteners; wetting agents such aslecithin, polysorbates, poloxamer, sorbitan monoesters, glycerylmonooleates, or laurylsulfates; and other therapeutically acceptableaccessory ingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular a syrup for diabetic subjects can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

The ingredients mentioned herein are not intended to be exhaustive, andone of skill in the art will be able to formulate suitable compositionsusing known or to be known ingredients.

Methylphenidate is being marketed in numerous dosage forms and atvarious dosage strengths either as a racemic mixture of d- andl-threo-methylphenidate or as a single d-threo-isomer (Table 1).Recommended daily doses depend on the dosage form, active ingredient(single isomer or racemic mixture) and individual subject or patienttitration.

TABLE 1 Examples of marketed methylphenidate dosage forms and dosagestrengths. Active Dosage Dosage Proprietary Ingredient Form Strength(s)Name(s) methylphenidate instant release 5, 10, 20 mg Ritalin ®hydrochloride tablet dexmethylphenidate instant release 2.5, 5, 10 mgFocalin ® hydrochloride tablet methylphenidate extended release 10, 20mg Methylin ER ®, hydrochloride tablet Metadate ER ® methylphenidateextended release 10, 18, 20, 27, 36, Concerta ® hydrochloride tablet 54mg methylphenidate chewable tablet 2.5, 5, 10 mg Methylin hydrochloridemethylphenidate extended release 10, 20, 30, 40 mg Ritalin LA ®hydrochloride capsules methylphenidate extended release 10, 20, 30, 40,50, Metadate CD ® hydrochloride capsules 60 mg dexmethylphenidateextended release 5, 10, 15, 20, 30, Focalin XR ® hydrochloride capsules40 mg methylphenidate transdermal 10, 15, 20, Daytrana ® patch 30 mg/9 hmethylphenidate oral solution 5, 10 mg/5 mL Methylin ® hydrochloride

In some embodiments, doses of the compositions of the presenttechnology, comprising the prodrug and/or its pharmaceuticallyacceptable salts, and unconjugated methylphenidate and/or itspharmaceutically acceptable salts, can be higher or lower than doses ofunconjugated methylphenidate depending on their molecular weight, therespective weight-percentage of methylphenidate as part of the wholeconjugate or conjugate salt, and their bioavailability (with respect toreleased methylphenidate). Therefore dosages may be higher or lower thanthe dosages of free methylphenidate. Dosages can be calculated based onthe strengths of dosages of methylphenidate hydrochloride which rangebetween, for example, but not limited to, about 0.5 mg and about 200 mgper dose. Dose conversion from methylphenidate hydrochloride tomethylphenidate prodrug can be performed using the following formula:

${{dose}\mspace{14mu}\left( {{MPH}\mspace{14mu}{prodrug}} \right)} = {f_{BA} \times {dose}\mspace{14mu}\left( {{MPH}\mspace{14mu}{hydrochloride}} \right) \times \frac{{MW}\mspace{14mu}\left( {{MPH}\mspace{14mu}{prodrug}} \right)}{269.77\frac{g}{mol}}}$

-   -   MPH=methylphenidate    -   MW=molecular weight    -   f_(BA)=correction factor accounting for differences in        bioavailability between unmodified methylphenidate and prodrugs        of the present technology. This correction factor is specific        for each prodrug.

In further embodiments, weight amounts or doses of unconjugated orconjugated d-methylphenidate, and any of their salt forms can beexpressed as the molar equivalent weight amount or dose of any othercompound or a salt thereof. For example, a dose ofd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride can alternatively be expressed asan equimolar dose of d-MPH-CO₂CH₂-nicotinoyl-L-Ser, d-methylphenidate,or d-methylphenidate hydrochloride. Other examples include, but are notlimited to, a dose of d-methylphenidate hydrochloride can alternativelybe expressed as an equimolar dose of d-methylphenidate,d-MPH-CO₂CH₂-nicotinoyl-L-Ser, or d-MPH-CO₂CH₂-nicotinoyl-L-Serchloride. The general formula to calculate the molar equivalent dose ofCompound 2 from the dose of Compound 1 is as follows:

${{Dose}\mspace{14mu}\left( {{Compound}\mspace{14mu} 2} \right)} = {{Dose}\mspace{14mu}\left( {{Compound}\mspace{14mu} 1} \right) \times \frac{{MW}\mspace{14mu}\left( {{Compound}\mspace{14mu} 2} \right)}{{MW}\mspace{14mu}\left( {{Compound}\mspace{14mu} 1} \right)}}$

-   -   Dose(Compound 1)=dose of Compound 1 (in mass units)    -   Dose(Compound 1)=dose of Compound 1 (in mass units)    -   MW(Compound 1)=molecular weight of Compound 1    -   MW(Compound 2)=molecular weight of Compound 2        The following table lists the molecular weights of unconjugated        d-methylphenidate and a salt form thereof, and an example of a        conjugated d-methylphenidate and a salt form thereof.

Molecular Weight Compound (g/mol) d-MPH—CO₂CH₂-nicotinoyl-L-Ser 500.53d-MPH—CO₂CH₂-nicotinoyl-L-Ser 535.98 chloride d-methylphenidate 233.31d-methylphenidate hydrochloride 269.77

In some embodiments, suitable dosages of the compositions of the presenttechnology include, but are not limited to, formulations including anamount of conjugated d-methylphenidate and unconjugated methylphenidateequimolar to an amount of unconjugated d-methylphenidate from about 0.1mg or higher, alternatively about 0.5 mg or higher, alternatively fromabout 1.0 mg or higher, alternatively from about 2.5 mg or higher,alternatively from about 5.0 mg or higher, alternatively from about 7.5mg or higher, alternatively from about 10 mg or higher, alternativelyfrom about 20 mg or higher, alternatively from about 30 mg or higher,alternatively from about 40 mg or higher, alternatively from about 50 mgor higher, alternatively from about 60 mg or higher, alternatively fromabout 70 mg or higher, alternatively from about 80 mg or higher,alternatively from about 90 mg or higher, alternatively from about 100mg or higher, alternatively 120 mg or higher, alternatively 200 mg orhigher, alternatively 300 mg or higher, and include any additionalincrements thereof, for example, about 0.1, about 0.2, about 0.25, about0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8,about 0.9 or about 1.0 mg and multiplied factors thereof, (e.g., about×1, about ×2, about ×2.5, about ×5, about ×10, about ×100, etc). Theamount of conjugated d-methylphenidate and unconjugated methylphenidatein the compositions of the present technology can vary from about 5% toabout 95% by weight, based on the total weight of the d-methylphenidateactive, including, but not limited to, amounts of about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, or any amounts in between, in increments of about 0.5%, about 1%,about 2.5%, or about 5%. In preferred embodiments, the amount ofd-methylphenidate contributed by the conjugated d-methylphenidate rangesfrom about 60% to about 95% by weight, based on the total weight of thed-methylphenidate active, and the amount of unconjugated methylphenidateranges from about 5% to about 40% by weight based on the total weight ofthe d-methylphenidate active.

It is contemplated that daily dosing regimens for some embodiments ofthe compositions of the present technology include, but are not limitedto, an amount of d-methylphenidate that is molar equivalent to a dose ofd-methylphenidate hydrochloride from about 0.1 mg to about 300 mg perday, about 0.5 mg to about 300 mg per day, alternatively about 1 mg toabout 100 mg per day, alternatively about 5 mg to about 80 mg per day,alternatively about 10 mg to about 40 mg per day, alternatively about 10mg to 200 mg per day, alternatively about 20 mg to about 120 mg per day,alternatively about 30 mg to about 100 mg per day, alternatively about40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mgper day, alternatively about 20 mg to about 40 mg per day, alternativelyabout 20 mg to about 60 mg per day, alternatively about 10 mg to about50 mg per day, alternatively about 20 mg per day, alternatively about 40mg, alternatively about 60 mg per day, alternatively 80 mg per day,alternatively 100 mg per day, alternatively 120 mg per day.

It is also contemplated that some embodiments of the compositions of thepresent technology would have a dosing regimen of one time a day,alternatively two times a day or less, alternatively four times a day orless. It is contemplated that some of the formulations of the presenttechnology would be provided in a unit dose form. “Unit dose form” heremeans a single entity of a solid therapeutic dosage form (e.g., 1capsule, 1 tablet) or a single volume dispensed from a non-solid dosageform (e.g., 5 mL of a liquid or syrup). Such a unit dose form can befrom about 0.5 mg to about 400 mg per day, alternatively from about 0.1mg to about 300 mg per day, about 0.5 mg to about 300 mg per day,alternatively about 1 mg to about 100 mg per day, alternatively about 5mg to about 80 mg per day, alternatively about 10 mg to about 40 mg perday, alternatively about 10 mg to 200 mg per day, alternatively about 20mg to about 120 mg per day, alternatively about 30 mg to about 100 mgper day, alternatively about 40 mg to about 80 mg per day, alternativelyabout 50 mg to about 70 mg per day, alternatively about 20 mg to about40 mg per day, alternatively about 20 mg to about 60 mg per day,alternatively about 10 mg to about 50 mg per day, alternatively about 20mg per day, alternatively about 40 mg per day, alternatively about 60 mgper day, alternatively 80 mg per day, alternatively 100 mg per day,alternatively 120 mg per day. The present technology also includesdosage formulations including currently approved formulations ofd-methylphenidate (See Table 1), where the dosage can be calculatedusing the above-noted formula determined by the amount ofd-methylphenidate hydrochloride. The present technology provides fordosage forms formulated as a single therapy or as a combination therapy.

In some embodiments, the compositions of the present technology canfurther comprise or be combined with one or more active ingredient(s),including but not limited to aripiprazole, atomoxetine, baclofen,clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol,levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron,pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride,tetrabenazine, topiramate, ziprasidone, and ziprasidone.

In some embodiments, suitable dosages of the compositions of the presenttechnology, comprising conjugatedd-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser chloride prodrugs andunconjugated methylphenidate and/or pharmaceutically acceptable saltsthereof, include, but are not limited to, formulations including anamount of conjugated d-methylphenidate and unconjugatedd-methylphenidate equimolar to an amount of unconjugatedd-methylphenidate from about 0.5 mg or higher, alternatively from about1.0 mg or higher, alternatively from about 2.5 mg or higher,alternatively from about 5.0 mg or higher, alternatively from about 7.5mg or higher, alternatively from about 10 mg or higher, alternativelyfrom about 20 mg or higher, alternatively from about 30 mg or higher,alternatively from about 40 mg or higher, alternatively from about 50 mgor higher, alternatively from about 60 mg or higher, alternatively fromabout 70 mg or higher, alternatively from about 80 mg or higher,alternatively from about 90 mg or higher, alternatively from about 100mg or higher, alternatively 120 mg or higher, alternatively 200 mg orhigher, alternatively 300 mg or higher, and include any additionalincrements thereof, for example, about 0.1, about 0.2, about 0.25, about0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8,about 0.9 or about 1.0 mg and multiplied factors thereof, (e.g., about×1, about ×2, about ×2.5, about ×5, about ×10, about ×100, etc). It iscontemplated that daily dosing regimens for some embodiments of thecompositions comprising the conjugated d-methylphenidate of the presenttechnology and unconjugated d-methylphenidate include, but are notlimited to, an amount of d-methylphenidate that is molar equivalent to adose of d-methylphenidate hydrochloride from about 0.5 mg to about 300mg per day, alternatively about 1 mg to about 100 mg per day,alternatively about 5 mg to about 80 mg per day, alternatively about 10mg to about 40 mg per day, alternatively about 10 mg to 200 mg per day,alternatively about 20 mg to about 120 mg per day, alternatively about30 mg to about 100 mg per day, alternatively about 40 mg to about 80 mgper day, alternatively about 50 mg to about 70 mg per day, alternativelyabout 20 mg to about 40 mg per day, alternatively about 20 mg to about60 mg per day, alternatively about 10 mg to about 50 mg per day,alternatively about 20 mg per day, alternatively about 40 mg per day,alternatively about 60 mg per day, alternatively about 80 mg per day,alternatively about 100 mg per day, alternatively about 120 mg per day.

It is also contemplated that some embodiments of the compositions of thepresent technology, comprising (a) conjugatedd-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser and/or pharmaceuticallyacceptable salts thereof, and (b) unconjugated methylphenidate and/orpharmaceutically acceptable salts thereof, would have a dosing regimenof one time a day, alternatively two times a day or less, alternativelyfour times a day or less. It is contemplated that some of theformulations of the present technology would be provided in a unit doseform. Such a unit dose form can be from about 0.5 mg to about 400 mg perday, alternatively from about 0.1 mg to about 300 mg per day, about 0.5mg to about 300 mg per day, alternatively about 1 mg to about 100 mg perday, alternatively about 5 mg to about 80 mg per day, alternativelyabout 10 mg to about 40 mg per day, alternatively about 10 mg to 200 mgper day, alternatively about 20 mg to about 120 mg per day,alternatively about 30 mg to about 100 mg per day, alternatively about40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mgper day, alternatively about 20 mg to about 40 mg per day, alternativelyabout 20 mg to about 60 mg per day, alternatively about 10 mg to about50 mg per day, alternatively about 20 mg per day, alternatively about 40mg per day, alternatively about 60 mg per day, alternatively about 80 mgper day, alternatively about 100 mg per day, alternatively about 120 mgper day. The present technology also includes dosage formulationsincluding currently approved formulations of d-methylphenidate (SeeTable 1), where the dosage can be calculated using the above-notedformula determined by the amount of d-methylphenidate hydrochloride. Thepresent technology provides for dosage forms formulated as a singletherapy or as a combination therapy.

In some embodiments, the compositions comprising conjugates ofd-methylphenidate and nicotinoyl-L-Serine to form prodrugs have one ormore advantages, including, but not limited to, reduced or improved sideeffect profile, formation of less potentially toxic metabolites,formation of less inactive metabolites, improved water solubility,reduced drug abuse potential and/or reduced interpatient variability inplasma concentrations as compared to unconjugated d-methylphenidate.

Synthetic Schemes

General synthetic schemes for preparing prodrugs of d-methylphenidateare disclosed in U.S. Pat. No. 9,079,928, which is herein incorporatedby reference. One or more protecting groups may be attached to anyadditional reactive functional groups that may interfere with thecoupling to d-methylphenidate. Any suitable protecting group may be useddepending on the type of functional group and reaction conditions. Someprotecting group suitable for use in the present technology include, butare not limited to, acetyl (Ac), tert-butyl (tBu), tert-butyoxycarbonyl(Boc), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz),9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB),3,4 dimethoxybenzyl (DMPM), p-methozyphenyl (PMP), tosyl (Ts), or amides(like acetamides, phthalimides, and the like).

In other embodiments, a base may be required at any step in thesynthetic scheme of preparing the prodrug of d-methylphenidate. Suitablebases include, but are not limited to, 4-methylmorpholine (NMM),4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine (DIPEA),lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), anyalkali metal tert.-butoxide (e.g., potassium tert.-butoxide), any alkalimetal hydride (e.g., sodium hydride), any alkali metal alkoxide (e.g.,sodium methoxide), triethylamine (Et₃N or TEA) or any other tertiaryamine.

Suitable solvents that can be used for any reaction at any step in thesynthetic scheme of preparing the prodrug of d-methylphenidate include,but are not limited to, acetone, acetonitrile, butanol, chloroform,dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide(DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol (IPA), isopropylacetate (IPAc), diisopropyl ether, tetrahydrofuran, toluene, xylene orwater.

In some embodiments, an acid may be used to remove certain protectinggroups. Suitable acids include, but are not limited to, hydrochloricacid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid, acetic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid and nitric acid. Forcertain other protecting groups, a catalytic hydrogenation may be used,e.g., palladium on charcoal in the presence of hydrogen gas.

In some embodiments, an anion exchange medium, anion exchange resin,strong or weak anion exchanger including but not limited to Dowex® 1×8chloride (available from Dow Chemical Co, Midland, Mich.) may be used toreplace anionic counter ions of the cationic conjugate with a specificnew counter anion such as a chloride ion.

In some embodiments, the prodrug is hydrophilic and thus more watersoluble than the unconjugated d-methylphenidate.

A synthetic scheme for preparing d-MPH-CO₂CH₂-nicotinoyl-L-Ser is asfollows:

1). Nicotinoyl-Ser(tBu)OtBu 1

To O-tert-Butyl-L-Serine tert-butyl ester (H-Ser(tBu)OtBu, 5.305 g,23.17 mmol) in DCM (250 mL) was added Et₃N (5.329 g, 53.29 mmol, 2.3eq.). The flask was cooled in an ice-water bath (˜5° C.). Nicotinoylchloride hydrochloride (4.331 g, 24.33 mmol, 1.05 eq.) was added in 7portions over 1 hr. After adding, the water bath was removed and thereaction was stirred for another hour. 60 mL of 5% NH₄Cl was added toquench the reaction. The DCM layer was further washed with brine (60 mL)and dried over Na₂SO₄. The product was purified by column (hexanes:ethylacetate, 1:1.3). 6.977 g of syrup was obtained. The yield was 93.4% andthe purity was 98%.

(2R, 2′R)-(+)-Methylphenidate hydrochloride 2 (d-threo isomer)

2 was made by resolution of d-threo-Methylphenidate hydrochloride 2 withO, O′-dibenzoyl-D-(+)-tartaric acid according to the method developed byMahavir Prashad (Tetrahedron: Asymmetry 1999, 10, 3111). The yield was40-42%.

(R)-Chloromethyl2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate 3

d-(+)-threo Methylphenidate hydrochloride (MPH.HCl) 2 (8.093 g, 30 mmol)in toluene (150 mL) was added DIPEA (12.4 mL, 75 mmol) under ice-waterbath (˜5° C.). Then chloromethyl chloroformate (5.029 g, 39 mmol) intoluene (50 mL) was added over 20 min at about 5° C. After adding, thereaction was stirred at about 5-10° C. for 40 min. 5% NH₄Cl (50 mL) wasadded to quench the reaction. The toluene layer was separated, washedwith brine (50 mL) and dried over Na₂SO₄. Solvent was evaporated to givecrude 3, which was purified by silica gel chromatography column(hexanes:ethyl acetate, 3:1) to give 9.833 g of syrup (solidified whenstored in freezer) and the yield was quantitative.

4).3-((S)-1-carboxy-2-hydroxyethylcarbamoyl)-1-(((R)-2-(2-(R)-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyloxy)methyl)pyridiumchloride d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser

Nicotinoyl-Ser(tBu)OtBu 1 (0.322 g, 1 mmol) and carbamate 3 (0.355 g,1.09 mmol, 1.09 eq.) were dissolved in acetone (10 mL). Then NaI (0.161g, 1.08 mmol, 1.08 eq.) was added. The reaction was refluxed for 1.5 hr.Upon cooling to room temperature, the reaction mixture was kept at roomtemperature for 2 hr. The solid (NaCl) was filtered off. The filtratewas concentrated and dried over vacuum for 1 hr to give amorphous solid0.778 g. The solid in 4 M HCl/dioxane (5 mL) was stirred at roomtemperature for 2 hr.

Solvent was evaporated and the remaining was coevaporated with DCM (2times 6 mL), and then dried over vacuum for 1 hr. to give amorphoussolid 0.667 g. It was dissolved in 10 mL of ethanol and treated withresin twice (2 times 1 g, Dowex 1×8, 200-400, Cl form, prewashed withwater and ethanol, wet). The filtrate after resin treatment wasconcentrated and dried over vacuum to give amorphous solid 0.617 g. Thesolid was dissolved in 10 mL of IPA with heating and then 5 mL of IPAcwas added. Crystals formed gradually. After 3 hr., solid was collectedand washed with IPA/IPAc (2:1, 3 times 1 mL), dried over vacuum. 437 mgof white solid (d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride) was obtained.The yield was 81.5% and the purity was 97.6%.

Preparation of Cationic Species of d-MPH-CO₂CH₂-nicotinoyl-L-Ser

The chloride salt of d-MPH-CO₂CH₂-nicotinoyl-L-Ser is dissolved inwater. The resulting solution contains freed-MPH-CO₂CH₂-nicotinoyl-L-Ser in cationic form.

A synthetic scheme for preparing d-MPH-CO₂CH₂-nicotinoyl-L-Thr is asfollows:

Nicotinoyl-Thr(tBu)OtBu 5

Nicotinoyl-Thr(tBu)OtBu was prepared with the same procedure asnicotinoyl-Ser(tBu)OtBu. The yield was 90.4%.

3-(((1S,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-1-(((R)-2-(2-(R)-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyloxy)methyl)pyridiumchloride

Nicotinoyl-Thr(tBu)OtBu 5 (0.336 g, 1 mmol) and carbamate 3 (0.355 g,1.09 mmol, 1.09 eq.) were dissolved in acetone (8 mL). Then NaI (0.161g, 1.08 mmol, 1.08 eq.) was added. The reaction was refluxed for 1.5 hr.Upon cooling to room temperature, the reaction mixture was kept at roomtemperature for 1 hr. The solid (NaCl) was filtered off. The filtratewas concentrated and dried over vacuum for 1 hr to give amorphous solid0.796 g. The solid in 4 M HCl/dioxane (5 mL) was stirred at roomtemperature for 2 hr.

Solvent was evaporated and the remaining was coevaporated with DCM (twotimes 6 mL), and then dried over vacuum for 1 hr. to give amorphoussolid 0.70 g. It was dissolved 10 ml of ethanol and treated with resintwice (two times 1 g, Dowex 1×8, 200-400, Cl form, prewashed with waterand ethanol, wet). The filtrate after resin treatment was concentratedand dried over vacuum to give amorphous solid 0.638 g. The solid wasdissolved in 4 ml of EtOH and then 6 mL of TBME was added. Crystalformed slowly. After 2 days, solid was collected and washed withEtOH/TBME (1:1, three times 2 mL), dried over vacuum. 390 mg of whitesolid (d-MPH-CO₂CH₂-nicotinoyl-L-Thr chloride) was obtained. The yieldwas 70.9% and the purity was 99%.

When conjugating d-methylphenidate via carbamate bond to a methyleneoxide linker which in turn is connected to the nitrogen of the pyridinering of a nicotinoyl-amino acid moiety unexpected differences insolubility and pharmacokinetics were observed between conjugates ofracemic threo-methylphenidate (i.e., d and 1 isomers in a 1:1 ratio) andconjugates of isomerically pure d-threo-methylphenidate andl-threo-methylphenidate. Moreover, these differences were not limited tovarying the chirality of methylphenidate with the same terminal aminoacid. Differences were also observed when the conjugate comprised thesame form of d-methylphenidate but different amino acids. The conjugatesd-MPH-CO₂CH₂-nicotinoyl-L-Ser, l-MPH-CO₂CH₂-nicotinoyl-L-Ser, andd-MPH-CO₂CH₂-nicotinoyl-L-Thr each have three chiral centers.

In one embodiment, the conjugate d/l-MPH-CO₂CH₂-nicotinoyl-L-Ser wasrecrystallized from a mixture (1:1) of isopropylalcohol (IPA) andisopropylacetate (IPAc) yielding approximately 45.2% of product (purityof about 98% by HPLC). A similar amount of d-MPH-CO₂CH₂-nicotinoyl-L-Serrecrystallized from IPA and IPAc (2:1) yielded approximately 81.5% ofproduct (purity of about 97.6% by HPLC). This result is nonobvious sincethe yield of the isomerically pure conjugate was significantly highereven though more IPA was used which would be expected to improve thesolubility of the conjugate. The results indicated thatl-MPH-CO₂CH₂-nicotinoyl-L-Ser has significantly higher solubility inIPA/IPAc when compared to d-MPH-CO₂CH₂-nicotinoyl-L-Ser (Formula I).

In another embodiment, the following compounds were dosed orally in ratsat equimolar doses: d-MPH.HCl, l-MPH.HCl, d-MPH-CO₂CH₂-nicotinoyl-L-Ser,l-MPH-CO₂CH₂-nicotinoyl-L-Ser, d-MPH-CO₂CH₂-nicotinoyl-L-Thr, andl-MPH-CO₂CH₂-nicotinoyl-L-Thr. As shown in FIG. 1 and Table 3, whencomparing d-MPH.HCl and l-MPH.HCl, the bioavailability of the d-isomerwas significantly higher vs the l-isomer. The d:l-isomer ratios of meanC_(max) and AUC were about 192% and 124%, respectively, as shown inTable 3). In addition, the T_(max) of l-MPH was longer (0.7 hours)compared to d-MPH (0.4 hours) (Table 2).

TABLE 2 PK parameters for d-methylphenidate and l-methylphenidate afteroral administration of d-MPH•HCl and l-MPH•HCl in rats. d-MPH•HCll-MPH•HCl Analyte d-MPH l-MPH C_(max) (ng/mL) 98.9 51.5 AUC(hours*ng/mL) 119.2 96.4 T_(max) (hours) 0.4 0.7

TABLE 3 d:l-isomer ratios for unconjugated d-methylphenidate after oraladministration in rats. unconjugated d:l Ratio MPH C_(max) 192% AUC 124%T_(max)  62%

As shown in FIG. 2, relative exposure to d-MPH and l-MPH released fromd-MPH-CO₂CH₂-nicotinoyl-L-Thr and l-MPH-CO₂CH₂-nicotinoyl-L-Thr,respectively, were reversed (d:l conjugate ratios of mean C_(max) andAUC were about 58% and 53%, respectively as shown in Table 4) whencompared to unconjugated d-MPH and l-MPH. The relationship betweenT_(max) for d-MPH-CO₂CH₂-nicotinoyl-L-Thr andl-MPH-CO₂CH₂-nicotinoyl-L-Thr (0.6 hours vs 1.1 hours, respectively asshown in Table 4) was similar compared to unconjugated d-MPH and l-MPH.

TABLE 4 PK parameters for d-methylphenidate and l-methylphenidate afteroral administration of d-MPH—CO₂CH₂-nicotinoyl-L-Thr andl-MPH—CO₂CH₂-nicotinoyl-L-Thr in rats. d-MPH—CO₂CH₂- l-MPH—CO₂CH₂-nicotinoyl-L-Thr nicotinoyl-L-Thr Analyte d-MPH l-MPH C_(max) (ng/mL)62.5 107.6 AUC (hours*ng/mL) 84.2 160.0 T_(max) (hours) 0.6 1.1

TABLE 5 d:l-isomer ratios for MPH—CO₂CH₂-nicotinoyl-L-Thr after oraladministration in rats. MPH—CO₂CH₂- d:l Ratio nicotinoyl-L-Thr C_(max)58% AUC 53% T_(max) 57%

As shown in FIG. 3, the conjugates comprising L-serine produced wereagain different from the L-threonine conjugates and from unconjugatedmethylphenidate. While peak exposure (C_(max)) to d-MPH and l-MPHreleased from d-MPH-CO₂CH₂-nicotinoyl-L-Ser andl-MPH-CO₂CH₂-nicotinoyl-L-Ser, respectively, were similar, overallexposure (AUC) was lower and T_(max) significantly shorter forl-MPH-CO₂CH₂-nicotinoyl-L-Ser (d:l conjugate ratios of mean C_(max) andAUC were about 94% and 73%, respectively as shown Table 7; T_(max) was1.0 and 0.6 hours for d-MPH-CO₂CH₂-nicotinoyl-L-Ser andl-MPH-CO₂CH₂-nicotinoyl-L-Ser, respectively, as shown in Table 6).

TABLE 6 PK parameters for d-methylphenidate and l-methylphenidate afteroral administration of d-MPH—CO₂CH₂-nicotinoyl-L-Ser andl-MPH—CO₂CH₂-nicotinoyl-L-Ser in rats. d-MPH—CO₂CH₂- l-MPH—CO₂CH₂-Analyte nicotinoyl-L-Ser nicotinoyl-L-Ser C_(max) (ng/mL) 99.7 106.4 AUC(hours*ng/mL) 116.9 159.5 T_(max) (hours) 1.0 0.6

TABLE 7 d:l-isomer ratios for MPH—CO₂CH₂-nicotinoyl-L-Ser after oraladministration in rats. MPH—CO₂CH₂- d:l Ratio nicotinoyl-L-Ser C_(max)94% AUC 73% T_(max) 182% 

In summary, the serine conjugates produced extended release of d-MPH andthe threonine conjugates produced a more effective and extended releaseof l-MPH. Thus, by changing the stereochemistry of methylphenidate, therespective prodrugs exhibited selective absorption and/or clearance ofd-MPH vs l-MPH. Results of the human PK study confirmed that at leastfor d-MPH-CO₂CH₂-nicotinoyl-L-Ser, d-MPH was effectively released in anextended-release fashion and absorbed into the systemic circulationfollowing oral administration.

Pharmaceutical Kits

In some embodiments, the present technology provides pharmaceutical kitscomprising a composition of the present technology that has increasedwater solubility than compared to the unconjugated d-methylphenidate. Insome embodiments, the pharmaceutical kit comprises a specific amount ofindividual doses in a package, each dose comprising a pharmaceuticallyand/or therapeutically effective amount of the composition comprisingthe prodrug or conjugate of the present technology and unconjugatedmethylphenidate. The pharmaceutical kit may further include instructionsfor use. In some other embodiments, the kit comprises oral thin films orstrips comprising the composition comprising the prodrugs or conjugatesof the present technology and unconjugated methylphenidate. In someother embodiments, the kit comprises one or more blister packscontaining the composition comprising the prodrug or conjugate of thepresent technology and unconjugated methylphenidate. It will beappreciated by one skilled in the art that, in some embodiments, the kitmay include individual doses that have different dosage amounts.

The present technology provides pharmaceutical kits for the treatment orprevention of any of the indications mentioned above, including ADHD,eating disorder, binge eating disorder, obesity, narcolepsy, chronicfatigue, sleep disorder, EDS, cocaine addiction, or drug withdrawalsymptoms in a subject. The subject may be a human or animal subject. Asused herein the term animal is used in the veterinary sense and does notinclude humans. Suitable human subjects include neonatal subjects,pediatric subjects, adolescent subjects, adult subjects, geriatricsubjects, elderly subjects and normative subjects. The kit comprises aspecific amount of the individual doses in a package, each dosecontaining a pharmaceutically and/or therapeutically effective amount ofat least one conjugate of d-methylphenidate of the present technologyand unconjugated methylphenidate. The kit can further includeinstructions for use of the kit, wherein the instructions for use of thekit may further comprise methods for treating or preventing any of theindications selected from the group consisting of ADHD, eating disorder,binge eating disorder, obesity, narcolepsy, chronic fatigue, sleepdisorder, EDS, cocaine addiction, or drug withdrawal symptoms in asubject. The specified amount of individual doses may be from about 1 toabout 100 individual dosages, alternatively from about 1 to about 60individual dosages, alternatively from about 10 to about 30 individualdosages, including, about 1, about 2, about 5, about 10, about 15, about20, about 25, about 30, about 35, about 40, about 45, about 50, about55, about 60, about 70, about 80, about 100, and include any additionalincrements thereof, for example, about 1, about 2, about 5, about 10 andmultiplied factors thereof, (e.g., about ×1, about ×2, about ×2.5, about×5, about ×10, about ×100, etc). One of skill in the art will appreciatethat some embodiments of the kit of the present technology may includegraduated individual doses (i.e. dose amounts that increase or decreaseover a period of time), and/or a graduated dosing regimen, andinstructions for use.

In certain embodiments, compositions of the present technologycomprising unconjugated methylphenidate and at least one conjugate ofd-methylphenidate can be used in neonatal, pediatric, adolescent, adultand/or geriatric subjects with ADHD. For example, in some embodiments,the present compositions can be used for a once-daily dosing with apotentially improved onset and a long duration of action attributes thatmay benefit neonatal, pediatric and/or adolescent subjects with ADHD.

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

EXAMPLES Example 1: d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser and UnconjugatedMethylphenidate

The plasma concentrations of d-methylphenidate were measured by LC-MS/MSover time. The oral plasma concentrations of d-methylphenidate releasedfrom d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser were compared with unconjugatedd-methylphenidate after oral administration in rats.

FIG. 4 demonstrates the PK curve achieved by thed-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser as compared with unconjugated formsand all of the specific pharmacokinetic parameter data is presented inTables 8-9. As shown in Table 8, 4.75 mg of conjugate(d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser) was used as compared to 2.39 mgunconjugated d-methylphenidate hydrochloride used, however, both had thesame amount of the d-MPH (mg/kg), which was 2.06 mg/kg. The humanequivalent dose for the conjugate was 0.8 mg/kg as compared to 0.4 mg/kgfor unconjugated d-methylphenidate.

TABLE 8 Comparison of prodrugs of d-methylphenidate with unconjugatedmethylphenidate dosed orally in rats. Dose d-MPH—CO₂CH₂- Dose Referencesnicotinoyl-L-Ser d-MPH•HCl Test Article (mg/kg) 4.75 2.39 d-MPH Content(mg/kg) 2.06 2.06 Human Equivalent Dose (HED) 0.8 0.4

As shown in Table 9, the conjugate ofd-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser has a mean AUC_(0-4h) ofd-methylphenidate of about 86.1 h×ng/mL±10.0 h×ng/mL when administeredorally to a rat when compared to unconjugated d-methylphenidate of about79.5 h×ng/mL±10.0 h×ng/mL. The conjugate has a mean C_(max) ofd-methylphenidate of about 51.3 ng/mL±10 ng/mL when administered orallyto a rat compared to unconjugated d-methylphenidate of about 96.6ng/mL±10 ng/mL. The conjugate has a T_(max) of d-methylphenidate ofabout 1.2 hours±10 hours when compared to unconjugated d-methylphenidateof about 0.4 hours±10 hours when administered orally to a rat.

TABLE 9 PK comparison of prodrugs of d-methylphenidate with unconjugatedd-methylphenidate dosed orally in rats. d-MPH—CO₂CH₂- PK Parameternicotinoyl-L-Ser (N) d-MPH•HCl (N) AUC_(0-4 h) (h × ng/mL) 86.1 (10)79.5 (10) C_(max) (ng/mL) 51.3 (10) 96.6 (10) T_(max) (h)  1.2 (10)  0.4(10)

As shown in FIG. 4, after 4.75 mg conjugate was fed orally to rats,plasma concentrations of d-methylphenidate released from the conjugateare increased from 0 to about 1.2 hours following oral administration ina rat when compared to unconjugated d-methylphenidate (2.39 mg) of about0.4 hour. Plasma concentrations of d-methylphenidate released from theconjugate are slowly increased from about 1.2 to about 4 hour followingoral administration in a rat.

As shown in FIG. 5 and Table 10, after 4.75 mg conjugate wasintranasally administered to rats, plasma concentrations ofd-methylphenidate released from the conjugate are substantially flatfrom about 0 to about 1 hour following intranasal administration in arat. However, after 2.39 mg unconjugated d-methylphenidate wasintranasally administered to rats, plasma concentrations ofd-methylphenidate released from the conjugate are dramatically increasedfrom about 0 to about 0.1 hour following intranasal administration in arat. Conjugated d-methylphenidate was about 6% AUC and 5% C_(max) ofunconjugated d-methylphenidate.

Similar to FIG. 5, FIG. 6 and Table 10 show that after 4.75 mg conjugatewas injected intravenously to rats, plasma concentrations ofd-methylphenidate released from the conjugate are substantially flatfrom about 0 to about 2 hours following intravenous administration in arat. However, after 2.39 mg unconjugated d-methylphenidate was injectedintravenously to rats, plasma concentrations of d-methylphenidatereleased from the conjugate are dramatically increased from about 0 toabout 0.1 hour following intravenous administration in a rat. Conjugatedd-methylphenidate was about 17% AUC and 12% C_(max) of unconjugatedd-methylphenidate.

TABLE 10 PK comparison of prodrugs of d-methylphenidate withunconjugated d- methylphenidate dosed intranasally and intravenously inrats. Intranasal (N) Intravenous (N) PK d-MPH—CO₂CH₂- d-MPH—CO₂CH₂-Parameter nicotinoyl-L-Ser d-MPH nicotinoyl-L-Ser d-MPH AUC_(0-1 h) 67.4(8) 1110.8 (9) 51.0 (8)  312.6 (9) (h × ng/mL) AUC_(0-2 h) n/a n/a 93.5(8)  534.9 (9) (h × ng/mL) C_(max) (ng/mL) 118.9 (10)  2561.6 (10) 62.8(10)  541.8 (10) T_(max) (h)  0.1 (10)   0.1 (10)  0.9 (10)   0.4 (10)

A study was conducted in humans to assess the pharmacokinetics (PK) of32 mg of d-MPH-CO₂CH₂-nicotinoyl-L-Ser (liquid, dissolved in water)compared with 36 mg of Concerta® (tablet) after oral administrationunder fasted conditions (the dose of 32 mg ofd-MPH-CO₂CH₂-nicotinoyl-L-Ser contains about 13.9 mg ofd-methylphenidate, which was about 10.9% lower compared to the about15.6 mg of d-methylphenidate in 36 mg of Concerta®). Twenty-four (24)healthy volunteers were enrolled in this open-label, single-dose,two-treatment, two-period PK trial.

FIG. 7 shows mean (N=24) plasma concentration-time profiles of intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser after a single dose of 32 mg wasadministered as an oral liquid. Plasma concentrations of intact prodrugwere increased from about 0 to about 2 hours following oraladministration in a human subject and slowly decreased to about 0 at 24hours post dose.

A study was conducted in humans to assess the pharmacokinetics (PK) ofthree different doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser Chloride (liquid, dissolved in water)at 8/64 mg, 12/56 mg, and 16/48 mg, as compared with 54 mg of Concerta®(tablet) after oral administration under fasted conditions. Forty-eight(48) healthy volunteers (12 per treatment arm) were enrolled in thisopen-label, single- and multiple-dose, four-treatment, one-periodparallel PK trial. Table 11 provides a comparison of the four treatmentsused in this study.

TABLE 11 Dose of Dose of Unconjugated Formula II Total Dose of d-MPHHCl¹ (d-MPH HCl)² d-MPH HCl³ Ratio of Percent Treatment (mg) (mg) (mg)Doses⁴ A 8 64 (32) 40 20/80 B 12 56 (28) 40 30/70 C 16 48 (24) 40 40/60D⁵ 27 — 27 — ¹d-MPH HCl = d-methylphenidate hydrochloride ²Formula II =d-MPH—CO₂CH₂-nicotinoyl-L-Ser-Cl; the amount in parentheses representsthe molar equivalent dose of d-MPH HCl to the dose of Formula II. ³TheTotal Dose represents the combined dose of unconjugated and conjugatedd-methylphenidate (Formula II) calculated by adding the dose in Col. 2and the dose in Col. 3 (expressed in mg of d-MPH HCl). ⁴Percent Dose =ratio of API dose (Col. 2 or Col. 3) and Total Dose (Col. 4); the Ratioof Percent Doses is shown as Percent Dose of unconjugatedd-methylphenidate (Col. 2)/Percent Dose of Formula II (Col. 3); alldoses are expressed in molar equivalent doses of d-MPH HCl ⁵In additionto 27 mg of d-MPH HCl, a 54 mg Concerta ® tablet also includes 27 mg ofI-MPH.Eligible subjects included healthy male and female volunteers betweenthe age of 18 and 55 years with a body mass index (BMI) between 18 and32 kg/m² and a body weight between 60 and 100 kg at screening. Theprimary objective of the study was to assess the single and multipledose pharmacokinetics of d-MPH-CO₂CH₂-nicotinoyl-L-Ser andd-methylphenidate following multiple doses of different combinations ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser Chlorideadministered orally once per day for 7 days in healthy volunteers underfasted conditions, compared to the same dosing regimen with a Concerta®tablet. After the 1st dose of study drug (Day 1), blood samples for PKwere collected at predose (0 hour; within 1 hour prior to dosing), andat 0.5, 1, 1.5, 2, 2.5, 3, 4.5, 6, 7, 7.5, 8, 8.5, 9, 10, 12, 13, and 24hours±5 minutes postdose. The 24-hr post-dose blood sample was takenbefore administration of the 2nd dose of study drug. After the 2nd, 3rd,4th, 5th and 6th dose of study drug (Days 2-6), blood samples werecollected at predose (within 10 minutes prior to dosing), and at 1.5 and8 hours±5 minutes postdose. The predose sample on Day 2 was the same asthe 24-hour postdose sample after the 1st dose. After the last dose (7thdose) of study drug (Day 7), blood samples for PK were collected atpredose (within 10 minutes prior to dosing), and at 0.5, 1, 1.5, 2, 2.5,3, 4.5, 6, 7, 7.5, 8, 8.5, 9, 10, 12, 13, 24, 36, 48, 60 and 72 hours±5minutes postdose.

FIGS. 8-13 provide d-methylphenidate plasma concentration-time profilesfor the three dose mixtures: 8/64 mg, 12/56 mg, and 16/48 mg ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, in adulthuman subjects. FIGS. 14-25 provide d-MPH-CO₂CH₂-nicotinoyl-L-Serchloride plasma concentration time profiles for the three dose mixtures.FIGS. 26-35 provide d-methylphenidate plasma concentration-time profilesfor each of the three dose mixtures: 8/64 mg, 12/56 mg, and 16/48 mg ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride comparedwith Concerta® 54 mg. PK data are provided for each of the dose mixturesand Concerta® in Tables 12-15, respectively.

FIG. 8 shows the mean (N=12) d-methylphenidate plasma concentration-timeprofiles following a single oral dose of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 8/64 mg, and following the7^(th) oral dose after multiple oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride administered to adult humansubjects once every 24 hours (steady state).

FIG. 9 shows the mean (N=12) d-methylphenidate plasma concentration-timeprofiles following a single oral dose of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 12/56 mg, and following the7th oral dose after multiple oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride administered to adult humansubjects once every 24 hours (steady state). In this 12/56 mg treatmentarm, two of the subjects had higher plasma concentrations ofd-methylphenidate compared to the other 10 subjects. As a result, themean (N=12) plasma concentration-time profiles shown in FIG. 9 arehigher than the mean (N=10) d-methylphenidate plasma concentration-timeprofiles calculated without these two outlier subjects.

The d-methylphenidate plasma concentration-time profiles calculatedwithout the two outlier subjects are shown in FIG. 10. FIGS. 11 and 12,respectively, show the mean d-methylphenidate plasma concentration-timeprofiles with and without the outlier subjects following a single oraldose of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride,and following the 7th dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride. It isunderstood that depending on race, up to about 4-5% of the generalpopulation metabolizes or breaks down methylphenidate more slowly thanthe rest of the population (“slow metabolizers”). Due to their slowermetabolism, the “slow metabolizers” take longer to break downmethylphenidate and, as a result, have higher plasma concentrations ofmethylphenidate. Not wishing to be bound by any theory, it is suspectedthat the outlier subjects may have been “slow metabolizers.”

FIG. 13 shows the mean (N=12) d-methylphenidate plasmaconcentration-time profiles following a single oral dose ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride, 16/48 mg,and following the 7th oral dose after multiple oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chlorideadministered to adult human subjects once every 24 hours (steady state).

As shown in FIGS. 8-13, oral administration of each of the threetreatment dose mixtures resulted in early absorption (immediate release)of d-methylphenidate followed by a slower extended release ofd-methylphenidate. The figures also show that an appreciableconcentration of d-methylphenidate remains in the bloodstream 24 hoursafter administration. Comparing dose 1 vs. dose 7 plasma concentrationsat 24 hours, it can be seen that there is a modest accumulation ofd-methylphenidate in the bloodstream after the 7^(h) dose.

FIG. 14 shows the mean (N=12) plasma concentration-time profile ofintact d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride following a single oraldose of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride8/64 mg, and following the 7^(h) dose after multiple doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chlorideadministered to adult human subjects once every 24 hours. FIG. 15 showsthe mean (N=12) plasma concentration-time profile of the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 8/64 mg following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chlorideadministered to adult human subjects once every 24 hours

FIG. 16 shows the mean (N=12) plasma concentration-time profile ofintact d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride following a single oraldose of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride12/56 mg, and following the 7^(th) dose after multiple doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 12/56 mgadministered to adult human subjects once every 24 hours. FIG. 17 issimilar to FIG. 16, but shows the mean (N=10) plasma concentration-timeprofiles calculated without the two outlier subjects. FIGS. 18 and 19,respectively, show the mean plasma concentration-time profiles of intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride with and without the two outliersubjects following a single oral dose of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 12/56 mg, and following the7^(th) dose after multiple doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 12/56 mg administered toadult human subjects once every 24 hours. As shown in FIGS. 18 and 19,the plasma concentration-time profiles for the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride are substantially the same. Thisindicates that the two outlier subjects did not metabolize the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride differently from the othersubjects in this treatment arm, further supporting the belief that thetwo outlier subjects may have been “slow metabolizers” ofd-methylphenidate.

FIG. 20 shows the mean (N=12) plasma concentration-time profile of theintact d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 12/56administered to adult human subjects once every 24 hours. FIG. 21 issimilar to FIG. 20, but shows the mean (N=10) plasma concentration-timeprofile calculated without the two outlier subjects.

FIG. 22 shows the mean (N=12) plasma concentration-time profile ofintact d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride following a single oraldose of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride16/48 mg, and following the 7^(th) dose after multiple doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 16/48 mgadministered to adult human subjects once every 24 hours. FIG. 23 showsthe mean (N=12) plasma concentration-time profile of the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride following 7 oral doses ofd-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 16/48 mgadministered to adult human subjects once every 24 hours

FIGS. 24 and 25, respectively, show the mean (N=12) plasmaconcentration-time profile of intact d-MPH-CO₂CH₂-nicotinoyl-L-Serchloride for each of the three dose mixtures following a single oraldose of d-methylphenidate HCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride,and following the 7^(th) dose after multiple doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride administered to adult humansubjects once every 24 hours.

As shown in each of the FIGS. 14-25, plasma concentrations of intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride were increased from about 0 toabout 2 hours following oral administration, and slowly decreased to <1ng/mL, showing negligible accumulation of the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride at 24 hours post dose. Comparingdose 1 vs. dose 7 plasma concentrations at 24 hours, it can be seen thatthere is a negligible accumulation of the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride in the bloodstream after the7^(th) dose. Significant plasma concentrations of the intactd-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride that gradually decrease suggestthat circulating prodrug levels contribute to the extended releaseprofile by continuously releasing d-methylphenidate over time.

FIGS. 26-35 show the plasma concentration-time profiles for each of thedose mixtures 8/64 mg, 12/56 mg, and 16/48 mg, compared to Concerta® 54mg. FIGS. 26-28, respectively, show the plasma concentration-timeprofiles for the 8/64 mg dose and Concerta®, 54 mg following a singleoral dose, following the 7^(th) oral dose after multiple oral doses, andfor 7 oral doses, each administered once every 24 hours.

FIGS. 29-31, respectively, show the plasma concentration-time profilesfor the 12/56 mg dose and Concerta®, 54 mg following a single oral dose,following the 7^(h) oral dose after multiple oral doses, and for 7 oraldoses, each administered once every 24 hours. FIG. 32 shows theconcentration-time profile following 7 oral doses of d-methylphenidateHCl/d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride 12/56 mg administered toadult human subjects once every 24 hours, with and without the twooutlier subjects.

FIGS. 33-35, respectively, show the plasma concentration-time profilesfor the 16/48 mg dose and Concerta®, 54 mg following a single oral dose,following the 7^(h) oral dose after multiple oral doses, and for 7 oraldoses, each administered once every 24 hours. As shown in FIGS. 26-28,29-31, and 33-35, the plasma concentration of d-methylphenidate isincreased from about 0 to about 4 hours following administration foreach of the dose mixtures, 8/64 mg, 12/56 mg, and 16/48 mg, whencompared to Concerta®, 54 mg. These Figures also show a more gradualdecrease in the plasma concentration of d-methylphenidate for the threedose mixtures when compared to Concerta®, 54 mg. It can also be seenfrom these Figures that the plasma concentration of d-methylphenidate isincreased at 24 hours for the three dose mixtures compared to Concerta®54 mg. Steady state exposure to d-methylphenidate is reached, by day 7(or earlier).

TABLE 12 PK parameters following oral administration ofd-methylphenidate HCl/d-MPH—CO₂CH₂-nicotinoyl-L-Ser chloride 8/64 mg.Analyte d-MPH—CO₂CH₂- Mean Parameter d-MPH nicotinoyl-L-Ser chlorideDose 1 C_(max) (ng/mL) 11.7 32.5 AUC₀₋₂₄ (h*ng/mL) 142.5 152.1 T_(max)(hours)[median] 2.2 [2]   1.5 [1.5] Dose 7 C_(max) (ng/mL) 15.5 36.1AUC₀₋₂₄ (h*ng/mL) 187.0 181.0 T_(max) (hours)[median] 1.6 [1.5] 1.6[1.5] Accumulation C_(max) (%) 33.5 11.2 AUC₀₋₂₄ (%) 31.3 22.6

TABLE 13 PK parameters following oral administration ofd-methylphenidate HCl/d-MPH—CO₂CH₂-nicotinoyl-L-Ser chloride 12/56 mg.Analyte d-MPH—CO₂CH₂- d-MPH nicotinoyl-L-Ser chloride Without WithoutMean Parameter All subjects Outliers All subjects Outliers Dose 1C_(max) (ng/mL) 19.3 17.5 24.2 24.1 AUC₀₋₂₄ (h*ng/mL) 192.6 153.6 125.1124.1 T_(max) (hours)[median] 1.7 [1.5] 1.6 [1.5] 1.6 [1.5] 1.6 [1.5]Dose 7 C_(max) (ng/mL) 23.8 20.9 25.6 25.9 AUC₀₋₂₄ (h*ng/mL) 270.2 207.6129.6 130.7 T_(max) (hours)[median]  1.9 [1.75] 1.75 [1.5]    2 [1.75]  2 [1.75] Accumulation C_(max) (%) 22.6 19.6 19.3 24.1 AUC₀₋₂₄ (%) 36.934.3 8.0 10.9

TABLE 14 PK parameters following oral administration ofd-methylphenidate HCl/d- MPH—CO₂CH₂-nicotinoyl-L-Ser chloride 8/64 mg.Analyte d-MPH—CO₂CH₂- Mean Parameter d-MPH nicotinoyl-L-Ser chlorideDose 1 C_(max) (ng/mL) 20.2 25.6 AUC₀₋₂₄ (h*ng/mL) 153.9 121.3 T_(max)(hours)[median] 1.7 [1.5]  1.6 [1.5] Dose 7 C_(max) (ng/mL) 23.8 25.9AUC₀₋₂₄ (h*ng/mL) 187.1 132.6 T_(max) (hours)[median] 1.7 [1.75] 1.7[1.5] Accumulation C_(max) (%) 19.5 16.7 AUC₀₋₂₄ (%) 24.8 20.6

TABLE 15 PK parameters following oral administration of Concerta ® 54mg. Analyte Mean Parameter d-MPH Dose 1 C_(max) (ng/mL) 11.2 AUC₀₋₂₄(h*ng/mL) 165.3 T_(max) (hours)[median]  7.8 [8.25] Dose 7 C_(max)(ng/mL) 12.6 AUC₀₋₂₄ (h*ng/mL) 176.6 T_(max) (hours)[median] 5.0 [3.5]Accumulation C_(max) (%) 13.4 AUC₀₋₂₄ (%) 13.2

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the technology and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

We claim:
 1. A method of treating attention-deficit hyperactivitydisorder (ADHD) or attention deficit disorder (ADD) in a human or animalsubject, the method comprising administering to the human or animalsubject a composition that comprises a combined therapeuticallyeffective dose of a) a pharmaceutically acceptable salt of unconjugatedmethylphenidate, wherein the pharmaceutically acceptable salt ofunconjugated methylphenidate is d-threo-methylphenidate hydrochloride;and b) a pharmaceutically acceptable salt of a compound, wherein thepharmaceutically acceptable salt of the compound has the followingstructure:


2. The method of claim 1, wherein the composition is in a dosage formselected from a group consisting of a sublingual, a gummy, a chewabletablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, atroche, a lozenge, an oral powder, a solution, a thin strip, an oralthin film (OTF), an oral strip, a rectal film, a syrup, a suspension,and a suppository.
 3. The method of claim 2, wherein the composition isformulated for oral administration.
 4. The method of claim 1, whereinthe composition provides a dose amount that is the molar equivalent to adose from about 0.1 mg to about 500 mg d-methylphenidate hydrochlorideper dose.
 5. The method of claim 4, wherein the composition provides adose amount that is the molar equivalent to a dose from about 1 mg toabout 400 mg d-methylphenidate hydrochloride per dose.
 6. The method ofclaim 4, wherein the composition provides a dose amount that is themolar equivalent to a dose from about 1 mg to about 300 mgd-methylphenidate hydrochloride per dose.
 7. The method of claim 4,wherein the composition provides a dose amount that is the molarequivalent to a dose from about 1 mg to about 250 mg d-methylphenidatehydrochloride per dose.
 8. The method of claim 4, wherein thecomposition provides a dose amount that is the molar equivalent to adose from about 2 mg to about 200 mg d-methylphenidate hydrochloride perdose.
 9. The method of claim 4, wherein the composition provides a doseamount that is the molar equivalent to a dose from about 5 mg to about150 mg d-methylphenidate hydrochloride per dose.
 10. The method of claim4, wherein the composition provides a dose amount that is the molarequivalent to a dose from about 10 mg to about 100 mg d-methylphenidatehydrochloride per dose.
 11. The method of claim 4, wherein thecomposition provides a dose amount that is the molar equivalent to adose from about 20 mg to about 80 mg d-methylphenidate hydrochloride perdose.
 12. The method of claim 1, wherein the composition is provided ina unit dose form, blister pack, roll, or bulk bottle.
 13. The method ofclaim 12, wherein the unit dose form provides an amount ofd-methylphenidate that is molar equivalent to from about 0.5 mg to about500 mg d-methylphenidate hydrochloride.
 14. The method of claim 1,wherein the pharmaceutically acceptable salt of the unconjugatedmethylphenidate contributes an amount of d-threo-methylphenidate activein the range of about 5% to about 95% by weight, based on the totalweight of the d-methylphenidate active in the composition, and thepharmaceutically acceptable salt of the compound contributes an amountof d-threo-methylphenidate active in the range of about 95% to about 5%by weight, based on the total weight of the d-methylphenidate active inthe composition.
 15. The method of claim 1, wherein the pharmaceuticallyacceptable salt of the unconjugated methylphenidate contributes anamount of d-threo-methylphenidate active in the range of about 10% byweight, based on the total weight of the d-methylphenidate active in thecomposition, and the pharmaceutically acceptable salt of the compoundcontributes an amount of d-threo-methylphenidate active in the range ofabout 90% by weight, based on the total weight of the d-methylphenidateactive in the composition.
 16. The method of claim 1, wherein thepharmaceutically acceptable salt of the unconjugated methylphenidatecontributes an amount of d-threo-methylphenidate active in the range ofabout 30% by weight, based on the total weight of the d-methylphenidateactive in the composition, and the pharmaceutically acceptable salt ofthe compound contributes an amount of d-threo-methylphenidate active inthe range of about 70% by weight, based on the total weight of thed-methylphenidate active in the composition.
 17. The method of claim 1,wherein the pharmaceutically acceptable salt of the unconjugatedmethylphenidate contributes a molar equivalent amount ofd-threo-methylphenidate active of about 1.3 mg, or about 2 mg, or about2.6 mg, or about 3 mg, or about 3.5 mg, or about 3.9 mg, or about 4 mg,or about 5 mg, or about 5.2 mg, or about 6 mg, or about 6.5 mg, or about7 mg, or about 7.8 mg, or about 9.1 mg, or about 10.4 mg, or about 11.7mg, or about 13.0 mg, or about 14.3 mg, or about 15.6 mg, or about 16.9mg, or about 18.2 mg, or about 19.5 mg, or about 20.8 mg; and thepharmaceutically acceptable salt of the compound contributes a molarequivalent amount of d-threo-methylphenidate of about 6.5 mg, or about13.1 mg, or about 19.6 mg, or about 26.1 mg, or about 32.7 mg, or about39.2 mg, or about 40 mg, or about 45.8 mg, or about 52.3 mg, or about58.8 mg, or about 60 mg, or about 65.4 mg, or about 70 mg, or about 71.9mg, or about 78.4 mg, or about 80 mg, or about 85.0 mg, or about 91.5mg, or about 98.1 mg, or about 100 mg, or about 102.7 mg, or about 120mg, or about 130 mg, or about 140 mg.
 18. The method of claim 1, whereinthe composition further comprises one or more excipients or one or moreadditional pharmaceutically active ingredients.
 19. The method of claim18, wherein the excipients are selected from the group consisting ofanti-adherents, binders, coatings, disintegrants, gel forming agents,fillers, flavors, colorants, glidants, lubricants, preservatives,sorbents and sweeteners.